NIDCR's complete FY 2007 Congressional Justification, with supporting budget tables, is available in a printer-friendly PDF version (402K).

This document provides justification for the Fiscal Year 2007 activities of the National Institute of Dental and Craniofacial Research (NIDCR). A detailed description of NIH-wide Fiscal Year 2007 HIV/AIDS activities can be found in the NIH section entitled “Office of AIDS Research (OAR).” Detailed information on the NIH Roadmap for Medical Research may be found in the Overview section.

INTRODUCTION

It is widely accepted that team science will be required to solve the most intractable complex diseases and conditions that face our Nation. The merging of once disparate scientific disciplines is already well under way in dental and oral health research. The NIDCR now supports the first regional oral cancer screening program that integrates highly informative molecular discoveries with traditional screening techniques. This seminal project likely will serve as a template for more effective and potentially life saving early detection programs for oral cancer throughout the United States and Canada . As highlighted below, this research group took an important step forward this year in establishing that some predictive molecular characteristics of early precancerous oral lesions can be integrated with an easy-to-use liquid dye called toluidine blue that has been around since the late 1940s.

The NIDCR is not only fostering greater integration across scientific disciplines, it is leading by example. Also highlighted this year is collaboration between NIDCR intramural scientists with expertise in the basic biology of the salivary glands and a National Cancer Institute scientist with expertise in radiation biology. This merging of scientific interests has established in preliminary animal studies that a compound called Tempol can reproducibly spare the salivary glands during radiation therapy. This represents one of the more promising research leads in years to prevent dry mouth as a potentially debilitating side effect of radiation treatment for head and neck cancer.

Research challenges abound, not only in oral cancer, but also in the fight against temporomandibular joint and muscle disorders, chronic orofacial pain, dry mouth, periodontal disease, dental decay and myriad other oral conditions that collectively affect millions of Americans. These diseases are by nature complex, variable in severity, and sometimes exceedingly difficult to treat. While many of the molecular pieces underlying these conditions have been assembled, solving the totality of these biological puzzles will require greater integration among the life sciences, physical sciences, computer sciences, materials sciences, and other areas of scientific expertise. Each discipline brings its own complementary perspective, suggesting unique approaches to cut through the inherent complexity of a research problem and accelerate discovery.

The NIDCR and the Centers for Disease Control and Prevention last year released the first report in over a decade on the status of the Nation’s oral health. These new data, based on a survey representing more than 256 million Americans, show that while the oral health of our Nation continues to improve, there is much work to be done. Improvements included up to 10 percentage points reduction in tooth decay among persons six years of age and older, a 13 percentage point increase in dental sealants among children and adolescents, and a six percentage point reduction in total tooth loss among older Americans[1]. As rewarding as these results are, many public health challenges await. Tooth decay among pre-school children increased, and unacceptable oral health disparities still remain for too many Americans. Through continued integration, and ultimately, translation of the most promising research findings into widely available new treatments, it stands to reason that future reports will reflect continued gains in our Nation’s oral health.

SALIVARY DIAGNOSTICS

During the past year, several reports in the popular press unveiled a future of saliva-based diagnostic tests. These stories highlighted the painlessness of collecting saliva, the broad range of informative biochemicals such as hormones and biomarkers that are naturally dissolved in the fluid, and the near real-time speed of obtaining results. As promising as these scenarios are, they depend on continued technological progress to more fully integrate the various miniaturized components, automate the testing process, and validate the results to be as good as or better than standard blood tests. Through the continued integration of biology with engineering, physics, and computer sciences, the necessary technological breakthroughs now are coming online, and in recent months preliminary data have been published to begin the process of validating the accuracy and practicality of salivary diagnostics.

Science Advance: Microchip Assay for Inflammatory Disease

A group of NIDCR grantees and colleagues have developed a novel silicon microchip detection system for measuring the levels of various substances in saliva, including DNA, electrolytes, and proteins. The system functions as an automated and fully integrated “lab on a chip.” First, the saliva is transported to a designated region of the silicon platform, and then microfluidic structures deliver a series of small-volume reagents for an array of chemical and immunologic reactions. The result of each reaction produces a clear, color-coded fluorescent signal.

Following up on their technological success, the scientists recently reported clinical success in detecting C-reactive protein in human saliva with their microchip assay system. C-reactive protein, a measurable sign of inflammation in serum, is elevated in people with periodontal disease and may be predictive of developing heart disease. In their studies with healthy volunteers and others with periodontal disease, the group demonstrated that the system could measure levels of C-reactive protein in the saliva of those with oral inflammation. Importantly, the scientists also found their microchip had sufficient sensitivity and specificity to detect the protein during the various stages of periodontal disease. These studies mark the initial lab-on-a-chip exploration of proteins in saliva associated with periodontal disease, and they also clear the way for additional comparisons of C-reactive protein levels in healthy people and those with periodontitis, in order to establish baseline parameters indicative of periodontal health and disease. Such parameters will enable clinicians to identify and address periodontal disease earlier in the disease process, using methods that are faster and more comfortable for patients. Traditionally, clinicians have monitored periodontal disease by periodically measuring 168 different points in the mouth with a small probe to assess the amount of supporting bone lost. The traditional procedure is time consuming, and some patients find it uncomfortable; even more significant, by the time a change can be observed, the damage i.e., bone loss, cannot be reversed.

Science Advance: Mitochondrial DNA in Salivary Diagnostics

Although the DNA double helix in the cell nucleus grabs all of the attention, there is another source of genetic material in our cells. It is the DNA of our energy-generating mitochondria. Scientists have discovered in recent years that alterations in mitochondrial DNA occur in several types of tumors linked to smoking, including head and neck cancer. Building on this earlier work, a team of NIDCR grantees and colleagues hypothesized that people with oral squamous cell carcinoma may have elevated levels of mitochondrial DNA in their saliva, and this elevation would be independent of other possible contributing factors, such as age and how often one smokes. To test this hypothesis, the scientists evaluated levels of two mitochondrial DNA genes called Cox I and Cox II in the saliva of 94 people with oral squamous cell carcinoma and 656 healthy volunteers. Cox I and Cox II, specific forms of the enzyme cyclooxygenase, are known to be involved in the development and growth of head and neck cancer. The group found Cox I and Cox II DNA levels were, on average, significantly higher in those with head and neck cancer compared to the healthy controls, and this difference was independent of other contributory factors. With further investigation they hope to determine the timing and the mechanism by which these changes occur during the development of the cancer. That knowledge can then be used to develop more effective diagnostic tests and therapies.

Science Advance: Early Success Using Saliva to Detect Oral Cancer

NIDCR grantees found they could assay for elevated levels of four distinct cancer-associated molecules in saliva and distinguish with 91 percent accuracy between healthy people and those diagnosed with oral squamous cell carcinoma. This so-called “proof-of-principle” study marks the first report in the scientific literature that distinct patterns of “messenger RNA” not only are measurable in saliva, but also can indicate a developing tumor. Messenger RNA (mRNA) is the molecular intermediate between gene and protein, serving as a chemical record that an individual gene has been expressed.

The scientists noted it may be possible with further refinement of the test, possibly by including additional cancer-linked mRNAs, to attain the necessary 99 to 100 percent accuracy required of commercial diagnostic tests for oral squamous cell carcinoma, the sixth most common cancer in the United States . The researchers noted that currently no biochemical or genetic diagnostic tests are commercially available for oral cancer, and they also suspected RNA patterns in saliva may be informative for other cancers and common diseases.

HEAD AND NECK CANCER

Advances in early diagnosis of head and neck cancers are particularly important to reducing the unnecessary disfigurement and death wrought by this horrific disease. The five-year survival rate for victims of oral and pharyngeal cancers is only 56 percent[2]. These survival rates have not changed much in the last 20 years, due in part to the late stage at which many cases are diagnosed.

Science Advance: New Lead in Tumor Angiogenesis

NIDCR supported scientists added a key new piece to the puzzle of how tumor cells induce new blood vessels to form and fuel their abnormal growth, a process called angiogenesis. They found that, in addition to the well-known strategy of secreting proteins to trigger angiogenesis, tumor cells also physically attach to a protein displayed on the surfaces of cells that line the walls of our blood vessels. This physical interaction, like a finger pushing a button, sends a signal within these cells to grow and sprout new capillaries.

The finding has potentially major implications for anti-angiogenic therapy, one of the most intensively pursued areas in cancer research. It suggests a future strategy of blocking not only the secreted molecules, but also the cell-to-cell contact. Moreover, the finding raises the intriguing possibility of directing growth-inhibiting drugs at the normal blood vessel cells to stop angiogenesis. The great appeal of this approach is that it blocks the development of capillaries that would feed the developing tumor at a physical site which is not prone to develop resistance to the therapy, a frequent problem in traditional chemotherapeutic approaches.

Science Advance: Cell Surface Enzyme Causes Cancer

NIDCR scientists and colleagues reported in animal studies that a single, scissor-like enzyme called matriptase can cause cancer. This finding marks the first report of a protein-cleaving enzyme, or protease, on the cell surface that can efficiently trigger the formation of tumor cells.

The scientists noted the exact function of matriptase in healthy human cells remains a bit of a mystery. Previous studies showed that cells comprising the outer lining, or epithelium, of nearly all human organs express the protease. They also suggest that matriptase might play a role in activating other membrane-bound proteins on the cell surface that are involved in signaling basic cellular activities, such as growth and motility, or movement. Unanswered, however, was the question of whether matriptase, when over-expressed and deregulated within the cell, might cause cancer. The scientists produced mice that expressed the human version of the gene in a stable, measurable manner to answer the question. They found that deregulated matriptase sends a strong, versatile pro-growth signal; a key point is that, like a classic oncogene, (cancer-causing gene) matriptase initiates the erroneous growth signal. Because of its accessibility on the cell surface, the scientists also noted that, with further study, matriptase may serve as an excellent molecular target to treat cancer.

Science Advance: Key Finding in How Tumor Cells Invade Healthy Tissues

To colonize a healthy tissue, cancer cells must degrade the extracellular matrix that encapsulates it. That means primarily degrading a ubiquitous structural protein called collagen. For decades, researchers have focused on how tumor cells co-opt the body’s own protein-degrading machinery to bore through the collagen. What has not been well studied is whether cells within the developing tumor also possess their own internal machinery to carry out the job.

NIDCR scientists and colleagues found that a recently discovered molecule called uPARAP/Endo180 not only is present on the surface of certain cells in a tumor, but it also serves as a switch that activates an internal process to degrade collagen. In fact, the scientists indicate this internal, or intracellular, pathway appears to play a major role in collagen degradation during tumor invasion. This seminal finding raises an important clinical issue. A number of cancer drugs are under study to prevent collagen degradation through the co-opting of the body’s protein-degrading machinery. Is it possible that tumors simply can compensate for the effects of the drugs by activating the intracellular degradation pathway?

PAIN AND NEUROSENSORY RESEARCH

The temporomandibular joints (TMJ) - where the jaw and skull bones meet on both sides of the head - are always in harm’s way. The TMJ is readily exposed to absorb blunt force to the head, and, because of its essential role in opening the mouth, the joint must absorb and process continuous mechanical stress throughout the day from chewing, talking, clenching, and even grinding one’s teeth at night. Given this heavy daily wear and tear, an estimated 10 million Americans today live with temporomandibular joint and muscle disorders (TMJMD), a group of at least 20 distinct pathologic conditions, which disproportionately affect women. Many additional individuals suffer from other chronic craniofacial pain pathologies such as trigeminal neuralgia.

NIDCR has a long been a leader in the area of pain research and management. By spanning the areas of basic, translational and clinical research, NIDCR’s pain research encompasses a broad array of scientific areas – from basic studies of the biology of pain to research on novel approaches to manage chronic and acute pain. Thus, it is natural that NIDCR pain and neuroscience research interfaces with two important NIH-wide initiatives. One is the NIH Pain Consortium, composed of representatives of NIH Institutes and Centers that support pain research and jointly led by NIDCR, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute for Nursing Research (NINR). In addition to member Institutes’ grants for pain research, recent activities included a conference on Women and Pain and a Science Writer’s Seminar on pain. A second program, the NIH Blueprint for Neuroscience Research, is a new initiative formed by 15 Institutes and Centers working collaboratively to fund large, innovative neuroscience research projects at NIH. Initiatives on neurodegeneration, which are planned for FY 2007, will be of interest to NIDCR researchers studying chronic orofacial pain disorders such as temporomandibular joint disorders.

New Initiative: Temporomandibular Joint and Muscle Disorders - Pathophysiological Mechanisms Linking Comorbid Conditions

Scientists long have noted that studying TMJMD can be problematic because many patients also battle co-existing chronic illnesses that contribute to, and often mimic, some of the symptoms of TMJMD. These painful conditions include: fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, irritable bowel syndrome, migraine headache, atypical facial pain, and trigeminal neuralgia. Further complicating the research, scientists know little about the underlying molecular and pathological mechanisms that link the symptoms of these associated conditions with TMJMD. Once these mechanisms are delineated, scientists will have a clearer view of the pathophysiology of these conditions, an understanding that is essential in learning to design targeted and more effective treatments for people with TMJMD.

This initiative will determine the fundamental causes of several painful conditions that are known to occur concurrently in people with TMJMD. By defining the underlying causes of these associated conditions, it will be possible to focus more clearly on their contributory role in the development, course, and persistence of TMJMD.

Science Advance: Genetics of Pain Perception

Over the years, scientists have identified a handful of human genes that are involved in pain perception. One is catecholamine-O-methyltransferase, or COMT, an enzyme that inactivates a certain type of nerve signaling compound called a neurotransmitter. NIDCR scientists, grantees, and colleagues recently recruited 202 healthy female volunteers at risk for TMJMD. The researchers analyzed the COMT gene sequence of each volunteer and discovered three common changes in the chemical structure, or spelling, of the gene. These changes, consisting of shared combinations of several repeated chemical “phrases” along the gene sequence, are called haplotypes. Importantly, the three haplotypes correlated with each volunteer’s baseline sensitivity to pain. The three haplotypes were designated: low pain sensitivity, average pain sensitivity, and high pain sensitivity.

After following 170 of the volunteers for many months, the researchers determined that those who had a low-sensitivity-to-pain haplotype were more than two times less likely to develop TMJMD. In addition, those with the low-sensitivity haplotype had much higher levels of COMT enzymatic activity compared to the other haplotypes - an observation consistent with animal studies in which inhibition of COMT produced “a profound increase in pain sensitivity.” The challenge now is to pursue this initial work and further define its diagnostic and prognostic usefulness for the treatment of TMJMD.

Science Advance: Scientists Decode Bitter Taste

Obesity, which is recognized as a growing health problem, is a complex condition. One gap in our knowledge that may help address obesity is a thorough understanding of how we taste our foods. The ability to sense bitter substances is one of five fundamental qualities of human taste, alerting us to noxious or even potentially toxic substances. In previous work, NIDCR scientists established that specialized protein receptors on the tongue and palate known as T2R receptors initiate the sensation that our brain recognizes as bitterness. Now the scientists and their colleagues have further decoded the molecular wiring involved in the process. The researchers reported that T2R receptor proteins not only are sufficient and necessary to detect bitter compounds, they vary between mouse and man. This evolutionary diversity helps to explain the differences in bitter taste responses between the species. The next step in the investigation was to determine the mechanism by which the T2R receptors confer the bitter sensation. When mice were engineered to express T2R receptors in sweet sensing cells, they became strongly attracted to the resulting “bitter” taste. Conversely, those that expressed the T2R receptor normally were averse to the same bitter taste that the specially bred sweet-sensing mice found so appealing. This finding illustrates that whether a compound tastes bitter or sweet is not a property of the molecule or even of the receptors that it activates, but rather because it activates a specific class of taste receptor cells that are hard-wired in the nervous system to elicit a specific sensation and reaction. This discovery may lead to the logical design of new compounds designed to modify taste, for example, in designing non-caloric sweeteners, sweeteners that can improve dental health or compounds that can block the intensely bitter taste associated with many medications.

ORAL BIOFILM

To date, researchers have identified over 400 different bacteria in the oral biofilm, also known as plaque, but they estimate this number may represent just over half of the microbial species there. This shortfall is due to the fact that many of these microbes cannot be cultivated in the laboratory or recovered in pure form. This makes it extremely difficult to understand how the biofilm functions as an intact community or to identify the subsets of microbes that interact to cause oral infections. As molecular-based techniques have matured in recent years, scientists have begun to make progress in completing the full roster of microbes that inhabit the oral biofilm, essential information in learning to fight periodontal disease, tooth decay, and other common oral conditions.

Science Advance: Chronic Periodontitis Involves More Oral Bacterial Species Than Previously Thought

For most of the 20th century, scientists extracted plaque from periodontal infections, placed it in a culture dish, and then compared the bacterial species that grew to those grown when the sample was taken from a healthy donor. This research led to the paradigm that a small subset of bacteria in the mouth, most notably gram-negative species of bacteria, such as Porphyromonas gingivalis, probably causes periodontal disease. However, some have begun to question this paradigm, and have suggested that many more bacterial species are involved than was traditionally believed. A team of NIDCR grantees recently added important new data to bolster this line of thinking.

NIDCR-supported researchers employed open-ended molecular based techniques - that is, cataloguing a broad array of the bacteria present, not just the known species - to compare the subgingival bacteria of a group of fifteen people in good oral health with another group of fifteen who had moderate to severe periodontitis. After identifying a total of 274 bacterial species in the samples, including six that were previously unidentified, the scientists found that 60 percent of these bacteria were from species that have not as yet been successfully grown in culture, meaning studies a decade or more ago would have missed them completely. The group also noticed that the bacterial profiles of healthy and diseased periodontal plaque donors differed in unexpected ways. Looking at the level of bacterial genera - clusters of related species - the researchers found several associations among the gram positives, rather than the gram negatives usually thought to be important in disease. They also noted that several of the newly identified bacteria outnumbered P. gingivalis and other species traditionally thought to play a role in periodontal disease. Taken together, these data suggest that chronic periodontitis is the result of global perturbation of the oral bacterial ecology rather than a site-specific microbial shift in the area of periodontal pocketing.

Science Advance: Study Finds Direct Association between Cardiovascular Disease and Periodontal Bacteria

In the early 20th century, scientists proposed that oral bacteria shed from chronic gum infections, enter the circulatory system, and possibly contribute to diseases of the heart and other body organs. This concept, known as the “focal infection theory,” fell out of fashion by the 1940s, and then resurfaced four decades later with the publication of new data proposing a link. Since then, a major sticking point in advancing the research has been simply how to pursue the hypothesis. Lacking the scientific tools to track oral bacteria in the body over several decades to determine if they directly trigger heart disease, most previous studies pursued indirect evidence. Conspicuously missing has been a large, well-designed study that in some way directly evaluates the role of the oral pathogens themselves.

In one of the first large, well-designed studies on the subject, an NIDCR grantee and colleagues reported that older adults who have higher proportions of four periodontal-disease-causing bacteria inhabiting their mouths also tend to have thicker carotid arteries, a strong predictor of stroke and heart attack. These data mark the first report of a direct association between cardiovascular disease and bacteria involved in periodontal disease, an inflammation of the gums that affects to varying degrees an estimated 200 million Americans. The researchers caution, however, that the findings are not proof that the bacteria cause cardiovascular disease, directly or indirectly. They noted that the more than 650 people in the study had their oral bacteria and carotid thickness evaluated at the same point in time, making it impossible to determine which comes first - the periodontal disease or thickening of the carotid artery. The scientists now are monitoring the participants over time in hopes of answering this question.

Science Advance: Important Clue into How Oral Bacteria Might Contribute to Endocarditis

Endocarditis is a sometimes life-threatening infection of the inner surface of the heart and/or its valves. Of the approximately 15,000 cases of endocarditis reported each year in the United States, many likely arise when bacteria that naturally attach to our teeth are displaced and pass into the bloodstream during a dental procedure, flossing, or even chewing food. These microbes while relatively harmless in the mouth, have an affinity for damaged endothelial cells or blood clots in the heart, where they attach, multiply, and form larger bacterial colonies that trigger the endocarditis. Scientists have shown that immune cells called monocytes are prominently found in early inflammatory lesions linked to endocarditis. What has been puzzling is that the monocytes tend to disappear from the lesions over time without becoming macrophages, scavenging immune cells formed from monocytes that remove debris from tissues, such as the damaged, bacteria-laden cells linked to endocarditis.

In studies with the well-known oral bacterium Streptococcus mutans, a team of NIDCR grantees showed that the usual monocyte-macrophage transformation rarely occurs. Instead, infected monocytes become dendritic cells, a type of immune cell that initiates an inflammation-producing immune response upon interaction with this bacterium. This finding indicates that changes in a person's normal immune response that are mediated by oral streptococci can contribute to endocarditis. It also suggests that an effective future strategy to treat endocarditis might involve learning to turn off the destructive immune response and/or reprogram the monocytes to produce macrophages to clear away the disease-causing bacterial colonies from the heart.

ORAL IMMUNOLOGY

Researchers have long recognized the involvement of oral bacteria in causing periodontal disease, tooth decay, and other common dental conditions. However, identifying the oral bacteria that are destructive to oral health is really just the first step in a much more complex research process. One must also know precisely how these oral microbes interact with our immune cells to spark the sometimes chronic inflammation of our gums, information that will point to specific proteins (for example, the C-reactive protein described earlier in this document) to target for improved periodontal therapy. As laboratory tools have improved in recent years, tremendous progress has been made to fill in the molecular details of this interaction, resulting in a range of discoveries with application not only to conditions in the mouth but throughout the body.

Science Advance: Anti Inflammatory Role of Omega-3 Fatty Acids Elucidated

Most Americans have listened to news stories extolling the anti-inflammatory health benefits of a diet rich in oily fish, such as salmon and mackerel, and their constituent polyunsaturated fat, omega-3 fatty acids. Left unanswered is the question of how omega-3 fatty acids protect against periodontitis, heart disease, arthritis, and other inflammatory conditions. A team of NIDCR grantees and their colleagues recently answered part of that question. They discovered that our bodies break down omega-3 fatty acids to yield important byproducts called resolvins, a newly discovered class of dietary fat. The scientists found that the subtype resolvin E1, in particular, helps to stop the migration of certain immune cells to sites of inflammation, thereby modulating the severity of (that is to say, resolving) the immune response. This is important, because many serious diseases (including periodontal and heart diseases as described earlier in this document) are thought to be the result of an overly exuberant response to inflammation by our bodies. Previously, the researchers found that aspirin also seems to prompt our bodies to produce resolvins. The scientists say they now are trying to develop large scale production methods for synthetic versions of resolvin E1 to enable larger scale studies that might elucidate additional information on mechanisms of action of this newly-discovered class of fatty acids, optimal therapeutic dosing levels for humans, etc., and possibly one day, to create medications for use in people with diseases caused or exacerbated by inflammatory response mechanisms.

New Initiative: Ontogeny of Host Innate Immune Recognition of, and Response to, Oral Microbes

At birth, our mouths contain hundreds of distinct bacteria, viruses, fungi, and other microbes. Some are potentially disease causing, but most are so-called “commensals.” The commensals obtain food and other benefits from inhabiting the mouth, but, in general, they neither harm nor help their human host. Many scientists have wondered why our innate immune system, which serves as our frontline defense against microbes throughout our lives, allows commensals to inhabit the mouth. The answer appears to be that commensals and the innate immunity that protects our oral mucosa, or gums, have co-evolved to ensure neither adversely affects the well being or survival of the other. The molecular basis for human-commensal mutualism is one of the fundamental questions in contemporary immunology, and this natural interaction is related to the longstanding quest for an explanation of how our innate immune system distinguishes self from non-self. For dental researchers, this question is particularly interesting because the innate immune system possesses the remarkable ability to discriminate between commensals and oral pathogens, even though many microbes display common structural motifs on their surfaces. By further clarifying the cellular and molecular mechanisms that underlie this discriminatory process, it may be possible in the future to target oral pathogens with greater specificity to prevent or treat periodontal disease, oral candidiasis, and tooth decay.

This initiative will define the cellular and molecular mechanisms involved in innate immune recognition over a lifetime. It will encourage research that explores which molecules on oral microbes are recognized by the innate immune system, how the system responds when it interacts with these microbes, and the contribution of saliva to this immunological process. At the same time, the initiative will foster studies to determine whether subtle genetic differences in a person’s DNA might influence the immune response to oral microbes, and what the connection is between our innate recognition of oral microbes and acquired immunity.

DENTAL MATERIALS

Virtually every American remains at risk for tooth decay. As a result, the disease continues to be a prominent public health problem. In fact, tooth decay remains the single most common chronic childhood disease - five times more common than asthma and seven times more common than hay fever[4]. For more than 40 years, dentists have placed tooth-colored dental composites into decayed teeth as an alternative to the traditional silver-colored amalgam restorations. However, most dental composites today still utilize the original matrix-forming molecules as their structural backbone. Despite steady progress in learning how to better formulate and cure, or harden, composites in a damaged tooth - particularly in larger back, or posterior, teeth - dentists still encounter the same basic laws of chemistry that confronted the inventor of composites. That is, a large composite filling shrinks, and stresses the tooth to which it is bonded. The accumulated stress increases the chances that the composite will need to be replaced prematurely and/or that the decayed tooth will crack, requiring more extensive repair. Given the seemingly unsolvable nature of the problem, innovative approaches are essential to introduce alternative methods that have the potential to propel the science of materials and restorative dentistry forward.

Science Advance: Promising New Polymer and Dental Material Discovered

Merging physics, chemical engineering, and materials science, NIDCR grantees and colleagues have developed a cross-linked polymer that reversibly cleaves its chemical backbone to allow for rapid stress relief during the curing process. Remarkably, the polymer does so without any degradation of its mechanical properties. The polymer mixture consists of two substances that produce a rubbery network. In addition to its potential usefulness in addressing problems with shrinkage of dental materials, this process may also be applied to a vast array of other biomedical or industrial applications for which the control or elimination of stress is critical.

New Initiative: Nanocomposite Materials for Dental Restorations

Nanotechnology stands out as one of the most promising areas of modern science. It involves the manipulation of matter at dimensions of roughly 1 to 100 nanometers (a nanometer is one billionth of a meter) to handcraft, atom by atom, unique molecules with novel applications, an idea that was hard to imagine just a generation ago. Preliminary work indicates that, on the nanoscale, dental researchers can more strategically influence the overall process of matrix formation and thereby enhance the structural integrity of composite dental materials.

Building on this initial work and its important potential benefits to dentistry and public health, the NIDCR will launch an initiative to produce a new generation of nanocomposite materials with enhanced adhesive bonding to the tooth surface, improved durability, better aesthetics, and maximum biocompatibility. The initiative will spur research to fabricate optimal nanoparticles as the structural building blocks for nanocomposites, create novel dental nanomaterials with greater wear resistance, evaluate the interaction of oral tissues with nanocomposites, produce novel nanofillers to act as key strengthening additives to composites, and evaluate the overall biocompatibility of the nanostructure materials.

DENTAL ENAMEL

The developmental biology of dental enamel remains one of nature’s most intriguing mysteries. The tissue starts to form in the tooth bud not as the hard, white substance so familiar to us in the mirror, but as a soft, protein-rich matrix specked with mineral crystals called hydroxyapatite. When a tooth finally erupts through the gums, nearly all of the original matrix has disappeared, leaving few clues to how its dominant protein, called amelogenin, orchestrates the mineralization process in the tooth bud. Solving this developmental mystery will be critical in learning to make artificial enamel, a vital step in one day engineering replacement teeth.

Science Advance: From Matrix to Microribbons

A team of NIDCR grantees and colleagues offered an intriguing structural glimpse into how amelogenin might orchestrate enamel deposition. They found in laboratory studies that amelogenin forms into spherical balls that in turn, assemble into long beaded chains. Because of their thin, ribbon-like appearance, the scientists called the chains “microribbons.” The scientists next dipped the microribbons into a mineralizing calcium-phosphate solution to determine whether they possess the structural integrity to serve as protein scaffolds for the mineralization process. The result: the microribbons yielded ordered hydroxyapatite crystals with similar orientation to those formed in enamel. This marks the first time that scientists have assembled amelogenin into ordered structures, mineralized them, and shown that the spherical balls, called nanospheres, are responsible for the ordered crystal growth that is essential to proper enamel formation, information that will be absolutely essential to understanding how enamel is formed in the tooth bud, and furthering the NIDCR’s ongoing goal to engineer the human tooth.

Science Advance: Measuring Toughness of the Dentin-Enamel Junction

Nature has brilliantly engineered our teeth to transfer mechanical stresses, such as chewing, to a thin, supportive region below the surface of the tooth, where our bony dentin and rigid enamel meet. This biologically complex region, known as the dentin-enamel junction, or DEJ, has captured the interest of dental researchers in hopes of better characterizing its stress-resistant capacity and its unique ability to prevent developing cracks in the outer enamel from spreading throughout the tooth and causing fractures. Despite the long-term research interest, largely missing from the scientific literature has been a comprehensive and technologically sophisticated analysis of structural variations and stress resistance across the DEJ, information that would greatly benefit the dental community. NIDCR grantees and colleagues recently provided this broad structural analysis and, based on their data, offered a new estimate of the toughness of the DEJ, characterizing the region as up to 10 times tougher than enamel but 75 percent less tough than dentin. They also concluded that a tooth's ability to stop the spread of cracks resides in the mantle dentin, i.e., the original layer of dentin laid down at the time of initial tooth formation, not in properties of the DEJ. This essential baseline information will allow academia and industry to develop dental products that better correspond to the structural dynamics of the tooth and therefore function better in the mouth. This knowledge may contribute to finding solutions to the “cracked tooth syndrome”, a problem that is becoming increasingly common among graying baby boomers.

NIH ROADMAP

The Roadmap’s three broad initiatives—New Pathways to Discovery, Research Teams of the Future, and Re-Engineering the Clinical Research Enterprise are synergistic with many recent and planned NIDCR activities, and the Institute directly supports awards under several Roadmap initiatives. For example, NIDCR participated in the development of the Roadmap Interdisciplinary Clinical Predoctoral (T32) Program; as a result, a number of the grantees include direct involvement of dental schools. Eighty percent (four out of five) of the recently awarded Multidisciplinary Clinical Research Career Development Programs grants involve dental school collaboration. Additionally, NIDCR directly supported awards for Supplements for Methodological Innovations in the Behavioral and Social Sciences.

Studies such as those designed to determine the linkages between oral infections and systemic conditions such as preterm birth and cardiovascular events have required collaborations among physicians, dentists and nurses. By integrating several disciplines in a more systematic way, the Roadmap initiative on Interdisciplinary Research Teams of the Future enables NIDCR’s ongoing inter- and multidisciplinary efforts to expand and develop new approaches to research. This initiative’s support of translational research and NIDCR-supported activities such as the recent “Pathway to Product Development” meeting are mutually reinforcing.

We anticipate that a number of dental schools will participate in the NIH Clinical and Translational Science Award (CTSA), a Roadmap initiative to catalyze the development of a new discipline of clinical and translational science. Their partnership and collaboration with schools of medicine, nursing, pharmacy, osteopathy, public health, engineering, and other clinically related entities is intended to create a new academic home for clinical and translational research that will capture, translate, and disseminate new scientific advances for the benefit of all Americans.

The scientific goals of the initiative Building Blocks, Biological Pathways and Networks are closely linked to NIDCR’s efforts to identify the full complement of genes, proteins and protein networks that are expressed in both oral cancer and periodontal disease. Advances in proteomic analysis platforms will be crucial for NIDCR to achieve its goal of defining the salivary proteome -- a key step in the Institute’s long-term goal to use oral fluids for diagnostic purposes. The Molecular Libraries and Molecular Imaging initiative may accelerate NIDCR’s progress in defining the molecular pathways of pain reception and in identifying new therapeutic targets to manage chronic pain. Researchers have developed powerful tools to extensively categorize the parts of cells in vivid detail, yet many questions remain to build "nano" structures that are compatible with living tissues. The NIH Nanomedicine Roadmap Initiative will be instrumental to NIDCR efforts on “Building the Tooth: Bridging Biology and Material Sciences.” For this initiative a biomimetics approach will be used to identify, at the nanoscale, the building blocks needed if we are to build a tooth and its associated structures.

Through these and similar efforts, the NIDCR is pleased to join with its sister Institutes to further the trans-NIH goal of boosting the resources and technologies needed for 21st century biomedical science.

INNOVATIVE MANAGEMENT AND ADMINISTRATION

To ensure that the Institute’s research agenda appropriately focuses on our mission, NIDCR has established a rigorous and more immediate science planning and priority setting process that feeds into the well-established annual budget process. These efforts are supported by a well-managed information technology infrastructure that relies on NIH enterprise IT systems and utilizes the latest technology to conduct business electronically. One example of NIDCR’s foresight in electronic business management lies in the relatively new SCORE system that integrates data on all Institute grants and contracts, and is designed to provide easy and rapid retrieval of information needed to respond to requests from a variety of government and public sources. NIDCR is actively engaged with other Institutes in implementing Grants.gov to receive and process grant applications. NIDCR’s IT investment is protected by its long-standing best practice of 100 percent patch management of commodity desktop computers, and patch management for non-commodity computers in all cases where it is practical to do so.

Last, to assure that we support research endeavors that truly reflect the Institute’s mission, we continue to have a robust evaluation program. Currently, an evaluation of NIDCR’s portfolio in oral health disparities research is underway and evaluations of our portfolio in craniofacial anomalies and the newly-funded General Dental Practice-Based Research Networks initiative are in the design phase.

Budget Policy

The Fiscal Year 2007 budget request for the NIDCR is $386,095,000, a decrease of $3,241,000 and 0.8 percent from the FY 2006 Appropriation. Included in the FY 2007 request is NIDCR’s support for the trans-NIH Roadmap initiatives, estimated at 1.2 percent of the FY 2007 budget request. A full description of this trans-NIH program may be found in the NIH Overview.

NIH’s highest priority is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while pursuing new research opportunities. We estimate that the average cost of competing RPGs will be $321,000 in FY 2007. While no inflationary increases are provided for direct recurring costs in noncompeting RPGs, where the NIDCR has committed to a programmatic increase for an award, such increases will be provided.

NIH must nurture a vibrant, creative research workforce, including sufficient numbers of new investigators with new ideas and new skills. In the FY 2007 budget request for NIDCR, $450,000 will be used to support 5 awards for the new K/R “Pathway to Independence” program.

NIDCR will also support the Genes, Environment, and Health Initiative (GEHI) to: 1) accelerate discovery of the major genetic factors associated with diseases that have a substantial public health impact; and 2) accelerate the development of innovative technologies and tools to measure dietary intake, physical activity, and environmental exposures, and to determine an individual’s biological response to those influences. The FY 2007 request includes $647,000 to support this project.

In the FY 2007 request, stipend levels for trainees supported through the Ruth L. Kirschstein National Research Service Awards will remain at the FY 2006 levels. The FY 2007 request includes funding for 8 research centers, 117 other research grants, including 90 career awards, and 17 R&D contracts. Intramural Research decreases by 0.5 percent. Research Management and Support increases by 1.5 percent. To cover the cost of pay increases, NIDCR will decrease the amounts budgeted for other cost categories such supplies, equipment, and services.

[1] Centers for Disease Control and Prevention. Surveillance for dental caries, dental sealants, tooth retention, edentulism, and enamel fluorosis— United States . 1988-94 and 1999-2002. In: Surveillance Summaries, August 26, 2005. MMWR 2005:54(NoSS-3).

[2] American Cancer Society. Cancer Facts and Figures 2003. Atlanta (GA): American Cancer Society; 2003.

[3] Ibid.

[4] U.S. Department of Health and Human Services. Oral Health in America : A Report of the Surgeon General—Executive Summary. Rockville, MD. 2000, p.2.

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