FY 2006 Congressional Justification

Authorizing Legislation: Section 301 of the Public Health Service Act, as amended.

Budget Authority

Additional Details - FY 2006 President's Budget Request

[3] Burdick AB: Genetic epidemiology and control of genetic expression in van der Woude syndrome. J Craniofac Genet Dev Biol Suppl. 2:99-105, 1986.

DENTAL CARIES

Despite dramatic reductions in tooth decay in the United States over the past 50 years, dental caries remains a significant public health problem, particularly among lower socioeconomic groups and certain racial/ethnic groups [4].

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

New Initiative:  New Technologies for Clinical Assessment of Enamel Demineralization

The NIDCR will launch an initiative to validate the effectiveness of high-resolution, real-time clinical imaging technologies and their ability to measure accurately the demineralization and remineralization of tooth enamel.   Some of the technologies that will be evaluated include:  fiber optic transillumination, digital imaging fiber optic transillumination, electrical conductivity measurement, quantitative light fluorescence, alternating current impedance spectroscopy, multi-photon imaging, infrared thermography, infrared fluorescence, optical coherence tomography, ultrasound, and terahertz imaging.

If these emerging technologies can be shown to accurately measure enamel mineralization, they would greatly facilitate clinical trials of revolutionary treatments to prevent or reverse tooth decay.  The initiative will stimulate much needed validation studies, including the application and refinement of new technologies for accurate and early assessment of tooth surface demineralization, the development of appropriate reference standards and validation protocols for them in caries research, and rapid implementation of proven technologies in future caries clinical trials.

ORAL BIOFILM

Biofilms are sticky, mat-like microbial communities that typically consist of hundreds of distinct organisms that cooperate with each other to adapt to changes in their environment and ensure their mutual survival.  These complex microbial communities are found throughout nature and most parts of the human body, including the mouth, where they can cause tooth decay, periodontal diseases, and other oral diseases.  To date, researchers have identified over 400 bacteria in the oral biofilm, but they estimate this number may represent only about half of the microbes there.  This shortfall has made it extremely difficult to understand how these microbial communities function as a unit or identify the subsets of microbes that interact to cause oral infections.  The NIDCR has begun supporting an innovative, three-year study to compile the first full catalogue of genes found in oral biofilms.  The study, which will yield many tens of thousands of new genes – exceeding the number found in the landmark Human Genome Project - will also attempt to detect unique patterns of genes and gene expression within these bacterial communities that are predictive of periodontal diseases, a leading cause of tooth loss that affects millions of  Americans[5].  Once found, these telltale patterns could lead one day to far earlier and more precise diagnosis and treatment of these diseases.  All of this biological information will be stored in a searchable online database that is accessible, free of charge, to researchers worldwide.  The database also will be home to an ambitious attempt to sort through the genes with sophisticated computer software and reassemble the genomes, or complete set of genes, for all of the organisms in the oral biofilms.  If successful, this would mean the entire genomes of bacteria that scientists previously could not grow or study in the laboratory would now be available for research.  The project will involve an increasingly popular technique called metagenomics, which has been used in recent years to study various environmental biofilms.  The NIDCR investigation marks the first time that this approach has been undertaken for biomedical research on humans.  

[5] Dye BA, Vargas CM:  The use of a modified CPTIN approach to estimate periodontal treatment needs among adults aged 20-79 years by socio-demographic characteristics in the United States, 1988-1994.  Community Dent Health 2002 Dec; 19(4):215-23.

Science Advance:  Archaea Contribute to Periodontal Diseases

Archaea are unicellular organisms that resemble bacteria but are evolutionarily distinct.  Among the three recognized groups of Archaea are the methanogens, whose name derives from their ability to synthesize methane gas for energy in anaerobic environments (i.e., environments without oxygen), including areas of the mouth such as periodontal pockets.  Several studies have reported previously that methanogens are present in the mouths of people with chronic gum, or periodontal, infections.  While interesting, these findings did not definitively link the methanogenic Archaea to the actual infections, leaving unanswered whether these organisms contribute to chronic periodontal disease, a condition that affects an estimated 35 percent of all adults in America[6]. If so, this would mark the first report in the medical literature of Archaea playing a role in human disease.

NIDCR grantees and colleagues detected methanogenic Archaea in 36 percent of people with chronic periodontitis.  The scientists showed that the more abundant the methanogenic Archaea were within the periodontal lesions, the more severe the infections tended to be.  Conversely, they found that the relative abundance of the Archaea decreased as the lesions improved with treatment.  This report provides the first clear evidence that Archaea can contribute to human disease.  Because Archaea also have been isolated from biofilms in the human gut and vagina, these findings point to an obvious need to study their possible contributions to other chronic inflammatory conditions.  Although the exact role of Archaea in periodontal disease remains to be elucidated, the researchers hypothesized that the Archaea may benefit from a symbiotic microbial relationship at the site of infection, possibly growing on fermented byproducts released by other oral pathogens.  If correct, in people with Archaea-positive periodontal disease, it may be possible to develop treatments that interfere with this symbiotic relationship and perhaps slow the infection.
 

Science Advance:  Scientists Finish Sequence of Oral Pathogen

In the late 1600s, Antonie van Leeuwenhoek, the renowned “father of microbiology,” peered through a microscope and noticed an unusual thread-like oral spirochete, a type of free-living bacterium that would later receive the name Treponema denticola.  More than 300 years later, a team of NIDCR grantees finished assembling the complete 2.8 million bases, or units of DNA, of Van Leeuwenhoek's microbe.  Although microbial genomes are now routinely sequenced, this organism could prove particularly interesting.  T. denticola is associated with periodontal diseases, and previous studies indicate T. denticola aggregates in the mouth with Porphyromonas gingivalis, which has long been suspected as one of the main causes of periodontal diseases.  Because the genome of P. gingivalis already has been fully sequenced, the T. denticola genome will allow scientists to more systematically study how these oral pathogens interact to cause disease.  Such studies could provide precise molecular clues on where to target new and potentially more effective therapies to prevent periodontal diseases.  T. denticola could serve as ideal prototype organisms to study the biology of spirochetes in general, which include human pathogens such as Treponema pallidum, which causes syphilis, and Borrelia burgdorferi, the source of Lyme disease.  With the full DNA sequence of T. denticola, the scientific community now has an excellent point of reference to study the biology of spirochetes, allowing them to define their basic biology, as well as compare the evolutionary adaptations that allow T. denticola and other organisms to survive in their own unique environment.

Science Advance:  Protein from Oral Pathogen Can Clear Medical Devices

Most people do not expect to get sick after being admitted to the hospital.  But hospital-acquired infections from bacteria-laden catheters are fairly common, with thousands of catheter-related bloodstream infections occurring in U.S. hospitals each year[7].  One of the main culprits is Staphylococcus epidermidis, a bacterium that inhabits the skin and mucous areas, such as the nose and mouth.  When a catheter is inserted into the body, Staph. epidermidis can produce a sticky slime that enables it to attach firmly to the instrument, grow into an adherent layer called a biofilm, and ultimately spread throughout the body.   Staph. epidermidis is resistant to many antibiotics, and doctors say they have few tools to thwart this ubiquitous bacterium from invading catheters. 

NIDCR grantees discovered in laboratory studies that a novel enzyme from an oral bacterium can stop Staph. epidermidis from attaching to hard surfaces.  The researchers showed that pre-coating catheters with the enzyme, called dispersin B, prevented the formation of a Staph. epidermidis biofilm.  This preventive activity lasted for at least a month and showed no signs of enzymatic breakdown, which would make it easy to store the precoated catheters in hospitals until they are needed.  With further development, the enzyme could be applied to coat catheters or other medical devices, potentially saving the American healthcare system millions of dollars each year.  It similarly could be applied to established biofilms to detach the bacterium from hard surfaces and/or consequently make it more sensitive to conventional antibiotic therapy.  The researchers also are pursuing whether dispersin B adversely affects other bacterial pathogens.

[7] Darouiche R, Device-associated infections: A macroproblem that starts with microadherence. Clin. Infect. Dis. 33: 1567-1572, 2001.

PAIN RESEARCH

People often think of “pain” as a general term to describe anything that ails them.  In truth, pain represents a spectrum of sensation, with different types of nerve and supportive cells interacting to communicate different aspects of the experience.  Because of its vast, web-like complexity of sensory inputs and outputs, pain can be extremely difficult to target and effectively treat, especially among the estimated 34 million adults with chronic pain conditions[8]. Opioid-based analgesics, the mainstay of current treatments for moderate to severe chronic pain, cannot provide universal relief, and other treatments are nonselective and/or can cause serious side effects.  These shortcomings have produced a tremendous need for novel approaches to pain management that, in combination with new and existing treatments, provide a broader range of relief from pain. 

[8] Foley KM, Gelband H (eds):  Improving Palliative Care for Cancer, Washington, D. C., National Academy Press, 2001.

New Initiative:  The Role of Neuronal/Glial Cell Interactions in Orofacial Pain Disorders

Sizeable gaps exist in our understanding of some of the most basic cells involved in the pain process.  Prime examples are the glial cells, of which there are three basic types:  microglia, oligodendrocytes, and astrocytes.  For decades, scientists assumed that glial cells primarily played a supportive role in the central nervous system and had no direct influence on the transmission of sensory signals to the brain.  But, as more powerful analytical molecular tools have emerged in recent years, scientists now realize that glial cells play a far more participatory role in pain than was previously appreciated.  With this new awareness, it becomes imperative to better define the biology of these cells and their roles in regulating certain aspects of nervous system function.   

The NIDCR will launch an initiative that will stimulate needed research into the basic biology of glial cells and their interactions with neurons in causing orofacial pain disorders, such as temporomandibular joint disorders.  The initiative will encourage multidisciplinary studies in the following areas:  (1) how activated glial cells (astrocytes and microglia) influence neurons in the actual biochemical transmission of pain in experimental pain models, (2) defining the mechanisms by which activated neurons signal the spinal cord, brain, and peripheral glial cells, (3) identifying proteins and signaling pathways within glial cells that maintain chronic pain states, (4) defining the neuronal proteins and pathways that glial cells activate, and (5) discovering novel therapeutic targets on activated glial cells.  Based on this broad investigative approach, key aspects of the pain process will be more clearly defined, pointing the way to unique and highly specific molecular targets for drug development.  

 Story of Discovery:  Variation on an Ancient Theme

More than 2,000 years ago, the Roman physician, Euphorbius, was among the first to tout the medicinal qualities of a spiny, cactus-like plant called Euphorbia resinifera.  Native to a remote region of Morocco, the plant contained a milky juice, which was dried into a resin and was widely prescribed as an irritant to counteract a range of problems from lethargy to snake bites.  As the centuries passed, E. resinifera lapsed into historical obscurity, until a team of scientists in the mid 1970s identified its active, irritating compound, which they gave the tongue-twisting name of resiniferatoxin, or RTX.  Among pain researchers, RTX soon became a popular laboratory tool because of its unique ability to bind to a much-studied protein called vanilloid receptor 1 (VR1), which is displayed on the surface of certain types of heat-pain-sensing neurons.  RTX attaches to VR1, and, like opening a window, prompts a brief influx of calcium ions through a channel, or pore, but only in those cells that manufacture the ion channel.

In 2001, Mike Iadarola and his colleagues at NIDCR published data showing the RTX-induced flow of calcium can overdose, seriously disable, and ultimately kill these neurons.  Because nerve cells in the peripheral nervous system first transmit their signals to the spine, where they then are processed and routed onward to the brain, their finding raised an intriguing therapeutic scenario:  The cell bodies of these peripheral neurons bundle together in groups near the spine, called dorsal root ganglia.  If RTX were applied directly to the ganglia, the scientists knew that they could selectively delete specific neurons that express large amounts of the VR1 protein on their surface.  By doing this, they wondered whether they could also permanently turn off their chronic pain signals, which are involved in severe arthritis, peripheral neuromas, trigeminal neuralgia, and advanced cancer?

As reported this year, Iadarola and colleagues performed a series of experiments in rats that showed a single injection into the trigeminal ganglion, which supplies sensation to the face, or into the cerebrospinal fluid that bathes the dorsal root ganglia, which supply sensation to the body, most likely deleted permanently a type of nerve cell called C-fiber neurons.  The same held true when they injected the drug into multiple ganglia that connect to the tail and hind legs. In both experiments, rats maintained their normal motor function as well as their ability to respond to other sensory stimuli, such as warm and very hot thermal stimulation and a mechanical pinch, an indication that RTX had only affected C-fiber neurons.  "This showed us that the deficit in terms of overall pain sensation was probably minimal," said NIDCR scientist Zoltan Olah, one of the inventors of the technology. "What were lost were the C-fiber neurons, which confer that sense of aching, chronic pain."

The group then applied the technique to dogs, whose owners had brought them into nearby veterinary hospitals with severe pain from arthritis and cancer.  "We were very encouraged to see a long-term therapeutic benefit that did not diminish with the progression of the disease," said Iadarola.  "When a cancer progresses, you often have to increase the dose of conventional pain medications, such as opiate analgesics, which can produce alterations of consciousness, activity level, and other severe side effects that can impair overall quality of life."  Based on these data, Iadarola said the RTX technique has tremendous potential in veterinary care.  But the group’s ultimate goal is to move the treatment into early stage clinical trials in the near future for people with severe chronic pain.

SALIVARY GLANDS

For many serious health conditions, early detection offers the best hope for cure.  However, many individuals obtain a diagnosis only after they experience symptoms, and then it may be too late.  Saliva and other oral fluids reflect serum levels of substances that may be useful for diagnostic applications, such as drugs, hormones, immunoglobulins, and toxic molecules.  Saliva is easy to collect and poses none of the risks, fears, or “invasiveness” of blood tests.

Miniaturization of the “lab on a chip” may allow placement of the detection device directly in the mouth, making sample collection unnecessary.  NIDCR is supporting an exciting initiative aimed at determining the efficacy of salivary diagnostics to monitor health and disease.  It is envisioned that by 2013, it will be possible to fabricate inexpensive technologies for the diagnosis of systemic and oral diseases in the privacy of one’s own home.  If successful, this line of research could yield improved detection for a number of diseases as well as dramatically reduce the cost and risk associated with blood test-based diagnostics.  Working in partnership with colleagues in industry and academia, scientists are already using microchip technology to develop salivary diagnostic tests that can be applied to a variety of conditions, including AIDS, oral infections, and potential agents of bioterror.  During the next phase of this initiative, NIDCR plans to support research that will complete the fabrication of a portable, automated microfluidics-based diagnostic device, validate the device, provide feasibility analysis of large-scale manufacture and test the device in clinical settings.

For decades, most biologists have subscribed to the idea that glands in the body either secrete proteins into the bloodstream, called endocrine secretion, or channel them outward through a duct, for example, to the mouth or to the intestine, called exocrine secretion.  But, according to the dogma, they cannot do both.  Salivary glands are an exception to the rule.  They not only secrete proteins into saliva then into the mouth in an exocrine manner, but also secrete proteins into the bloodstream in an endocrine fashion.  This dual secretory feature has made the salivary glands an intriguing, though often overlooked, target for gene therapy experiments.  In theory, the salivary glands could be used to treat oral and systemic conditions or even single-protein deficiency disorders, such as Type I diabetes mellitus, human growth hormone deficiency, and erythropoietin-responsive deficiencies.  The great potential advantage of gene therapy is that only one gene delivery infusion is needed, instead of multiple injections, making it less expensive and potentially easier to tolerate for patients.  Additionally, therapeutic genes injected into the salivary gland could provide a higher local concentration of medication than is possible with general injections into blood or muscle.

Science Advance:  Gene-Expression System Produces Stable Release of Growth Hormone

Although gene therapy has shown much promise over the past decade, one of its major challenges continues to be controlling the expression of a transplanted gene once it has been delivered into a cell.  As many scientists already have reported, transplanted genes may switch off prematurely, or, in some cases, they might not turn off fast enough, causing an undesirable overproduction of its replacement protein.  One way around this problem is to control the expression of the transplanted gene with a system controlled by a small molecule, for example rapamycin, a well-characterized drug that is frequently taken by organ transplant patients.  As scientists have envisioned the strategy, they stitch a chemical switch next to the gene that only rapamycin (or derivative) molecules can control.  Upon administration of the drug, the gene will turn on leading to protein production.

A team of NIDCR scientists succeeded in getting the so-called "rapamycin gene-activation" system to work in the salivary glands.  The scientists showed that the production of human growth hormone (hGH) and its secretion into the saliva of rats could be induced, or activated, with rapamycin at least three times in 16 days.  They found only a small amount of hGH in the blood compared to saliva, showing the salivary gland released this protein in the same manner as the pituitary gland normally does. 

Science Advance:  Gene Vector Performs Well in Animal Studies

Two years ago, NIDCR scientists constructed a new version of a gene-carrying vehicle, or vector, which functioned well in the salivary glands of mice for several weeks.  Most significantly, the vector - a stripped down, bioengineered version of the harmless adeno-associated virus (AAV) - had done so without triggering a sustained immune response, a common setback in gene therapy experiments.  Left unanswered, however, was whether the AAV gene vector could keep up the good work for several months or a year.

NIDCR scientists found that the AAV vector performed extremely well in the salivary glands of mice for at least one year.  The vector carried the gene for human erythropoietin, a hormone produced primarily in the kidneys to stimulate the production of red blood cells.  After injecting the vector into the submandibular salivary glands, they began to detect a gradual increase in serum levels of the human erythropoietin over the first 12 weeks, a sign that the salivary gland was producing the hormone and pumping it into the bloodstream.  Thereafter, serum levels of the human erythropoietin remained relatively stable to the 54-week mark.  Importantly, they detected no signs of an adverse immune response in the salivary glands.  These results clear the way scientifically to begin work in larger animals, which would allow the scientists to better scale the likely therapeutic dosage for humans for possible clinical trials. 

New Initiative:  Sjögren’s Syndrome as a Model for Complex Diseases

Sjögren’s syndrome is a systemic autoimmune disorder that involves any or all of the following symptoms:  dry mouth, dry eyes, and rheumatoid arthritis.  The syndrome affects perhaps as many as four million Americans and disproportionately occurs in women at a ratio of nine to one[9]. Because its cause is not well understood, highly specific and detailed diagnostic criteria are lacking.  In fact, people typically live with the syndrome’s ill effects from six to 10 years before receiving the diagnosis.  Just as significantly, no effective treatment is now available to control or reverse the underlying causes of Sjögren’s syndrome.  For those with oral complications, their salivary glands develop varying degrees of autoimmune damage, leading to reductions in their normal flow of saliva.  This places them at greater risk for caries and mucosal infections such as candidiasis and dysphagia.  They also must cope with the daily irritation of a dry mouth with its adverse effects on chewing, swallowing, and even speaking.

The NIDCR will organize an initiative to explore the complex biological and environmental interactions that trigger Sjögren’s syndrome.  A strong emphasis also will be placed on developing novel diagnostic, preventive, and therapeutic tools for the condition.  Recent advances in genomics, proteomics, combinatorial chemistry and other areas of science now make possible comprehensive studies of complicated conditions like Sjögren’s syndrome.  This initiative will employ these and other emerging technologies to elucidate the multifactorial etiology of the syndrome.  Among the issues addressed will be:  identifying genetic risk factors in humans, developing appropriate animal models, determining the initiating events that trigger the syndrome, teasing out its immunological aspects, identifying biological markers of developing disease, and generating relevant outcome measures for clinical trials of new therapeutics that treat all manifestations of Sjögren’s syndrome.  Because Sjögren’s syndrome is recognized as an outstanding “model” to study complex disease, the knowledge gained from this initiative could have broader application for understanding the biological and environmental interactions underlying other complex conditions.  

HEAD AND NECK CANCER

Science Advance:  Human Papillomavirus and Risk of Head and Neck Cancer

Previous research has identified a link between the presence of human papillomavirus (HPV) and the risk for developing head and neck cancer.  This finding opens up the possibility of using HPV as an independent predictor of risk for this malignancy.  Following up on this lead, NIDCR-supported scientists used an oral rinse to recover cells that normally are shed in the mouth.  They examined the presence of oncogenic, or high-risk, HPV in the cells of head and neck cancer patients and compared them with persons of similar age and gender without the disease.  They found that high-risk HPV types were detected in the oral cells from 23 percent of cancer patients compared to only 11 percent of the control subjects.  In addition, the researchers showed that the HPV type detected in the oral cells was similar to the HPV type detected in the tumor tissue at the time of diagnosis.  This finding suggests that detecting HPV from oral cells collected at the time of diagnosis but before treatment may be predictive of an HPV-related head and neck cancer.  Findings that HPV high-risk types can be detected from oral exfoliated cells from an oral rinse are noteworthy and might eventually lead to the development of a screening test to prevent oral cancer or to detect the disease during its earliest stages.  

Science Advance:  Scientists Discover Role of Protein in Tumor Cell Invasion

Scientists have recognized that bone sialoprotein (BSP) is elevated in the tumors and blood of people with breast and certain other developing cancers, a rise that sometimes can be associated with the spread of cancer cells throughout the body.  What has remained unclear is exactly how BSP might play a role in this process.

NIDCR researchers and colleagues reported for the first time that BSP forms a complex with two other proteins, possibly enabling cancer cells to better degrade the tissue that surrounds them and break free from tumors.  From there, the cells can distribute throughout the body and colonize other tissues, a process called metastasis.  The discovery could mark this protein complex as a potential target to prevent tumor metastasis.  Although the data are based on laboratory work, the scientists said they provide a viable target to explore the molecular dynamics of metastasis and potentially to intervene in the cancer process.  It is estimated that 350,000 people die with bone metastases annually in the United States[11].  If people at high risk of bone metastases can be identified early, treatment with bisphosphonate therapy, which suppresses the degradation of bone induced by tumor cells, can be initiated immediately.  The scientists also noted that their data have potential to be applied to the dental clinic, where this protein complex could be used to distinguish between suspicious oral lesions and aggressive early tumors.    

[11] Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-593

DENTAL IMPLANTS

Since their introduction in North America over 20 years ago, dental implants have become associated with a variety of designs, types, and surgical protocols.  However, few clinical trials have been conducted that adequately compare the various surgical and prosthetic protocols, their success in different locations of the mouth, the potentially compromising effects of systemic disease, and patient outcomes over time.

New Initiative:  Clinical Research on Osseointegrated Dental Implants

The NIDCR will begin an initiative to expand the body of high quality, scientific evidence that is available to patients and practitioners on the successful implantation of osseointegrated dental implants.  Patients and practitioners would benefit greatly from a series of clinical trials that explore these critical issues and provide objective scientific data to better inform their choices.  This initiative will compare outcomes of the various surgical and prosthetic protocols now used in the field.  Examples include immediate versus delayed placement, implant placement following various types of osseous grafting, immediate functional loading versus delayed functional loading, and implant needs in children who have congenitally missing teeth or suffer developmental disabilities.  Another area of opportunity is the assessment of the influence of systemic diseases, such as osteoporosis and diabetes, on success rates.  Lastly, studies will be conducted to evaluate patient preferences and quality of life compared to other prosthetic methods, such as dentures, for restoring the dentition.

HIV INFECTION AND HIV-RELATED OPPORTUNISTIC INFECTION

Oral complications of HIV infection have been recognized since the onset of the AIDS epidemic and remain a significant public health problem, affecting an estimated 30 to 80 percent of HIV-positive individuals[12].  These complications include: oral tumors, oral candidiasis, oral viral infections, salivary gland disorders, and oral ulcerations.  These conditions can be quite painful and directly contribute to a loss of appetite and wasting in individuals who develop AIDS.

[12] Patton LL, McKaig R, Strauss R, Rogers D, Enron JJ Jr., "Changing prevalence of oral manifestations of human immunodeficiency virus in the era of protease inhibitor therapy,"  Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:299-304, 2000.

New Initiative:  Protein Profiles of the Oral Mucosal Tissues in the Context of HIV/AIDS

The NIDCR will support an initiative to characterize changes in protein profiles and protein-protein interactions within the oral mucosa following HIV exposure and disease.  The oral mucosa is more resistant to HIV infection than other mucosal sites in the body.  This is of great interest scientifically because most HIV infections initiate in mucosal tissues.  If the anti-HIV factors in the oral mucosa can be elucidated more clearly, the new knowledge could lead to novel strategies to combat the virus and fight oral and other AIDS-related opportunistic infections.  As a critical first step in this direction, this initiative will support studies that comprehensively catalogue the patterns of protein expression in healthy oral mucosa and under varying degrees of HIV resistance and infection.  Because the oral mucosa is exposed to myriad external factors, ranging from immune cells to changes in oral pH, it is likely that the onset of oral HIV infection involves a convergence of internal and external factors.  This initiative will employ proteomic strategies to explore these complex biological interactions and better define the process of HIV resistance and infection.

New Initiative:  Research on Oral Manifestations of HIV-Related Immunosuppression

Traditionally, research into the oral manifestation of HIV infection has involved a single scientific discipline or one-time multidisciplinary collaborations.  However, given the biological complexity of these oral complications, a more dedicated teaming of researchers from complementary areas of science could greatly accelerate the pace of discovery and ultimately the development of improved treatments. 

The NIDCR will launch an initiative that will enable multidisciplinary scientific teams to study the oral manifestations and complications associated with HIV/AIDS-related immunosuppression.  This initiative will seed the formation of several multidisciplinary teams to pursue projects within a related biological theme.  This approach will expand the number of investigators interested in oral AIDS and has the potential to attract distinguished scientists from an array of disciplines.

NIH ROADMAP

• The initiative Building Blocks, Biological Pathways and Networks -- seeks to create a better “toolbox” for researchers, including innovative ways for capturing real-time images of molecular and cellular events that occur in the human body.  The scientific goals of this initiative 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. 
  
• The Interdisciplinary Research Teams of the Future initiatives will stimulate new mechanisms to facilitate the conduct of multi- and interdisciplinary research.  NIDCR’s work, particularly in areas such as Sjögren’s syndrome, cleft lip and palate, ectodermal dysplasia, cancer, chronic pain, and infectious diseases has traditionally included researchers from many disciplines.  Ongoing studies, 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, this Roadmap initiative will enable NIDCR’s ongoing inter- and multidisciplinary efforts to expand and develop new approaches to research.
  
• The Re-engineering Clinical Research initiative will promote the creation of better integrated networks working on clinical research that include community-based health care providers.  The integration of dentists in this new clinical research infrastructure is key, given that certain systemic conditions such as diabetes, Sjögren’s syndrome, HIV/AIDS and osteoporosis have important oral symptoms, manifestations or complications.  NIDCR’s General Dental Practice-Based Networks in time, will link with existing medical networks supported through the Roadmap initiative to provide additional patients, professional expertise, and integration of resources for conducting research across a broad spectrum of health care specialties.  These practice-based dental networks will, upon the completion of the NIH Roadmap "Networks/NECTAR" feasibility studies, position the dental research community to participate in the next stage of related Roadmap initiatives.
• Nanotechnology involves the creation and use of materials and devices at the level of molecules and atoms.  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 and can safely operate inside the body.  The NIH Nanomedicine Roadmap Initiative will be instrumental to NIDCR’s efforts by providing extensive information about the physical properties of intracellular structures that will inform us about how biology's molecular machines are built. 
•  Finally, the NIDCR is directly supporting awards under several of the Roadmap initiatives, including those for Short Programs for Interdisciplinary Research Training and Supplements for Methodological Innovations in the Behavioral and Social Sciences.
  
  

THE NIH NEUROSCIENCE BLUEPRINT

Overview -- The Blueprint is a framework to enhance cooperation among fifteen NIH Institutes and Centers that support research on the nervous system.  Over the past decade, driven by the science, the NIH neuroscience Institutes and Centers have increasingly joined forces through initiatives and working groups focused on specific disorders.  The Blueprint builds on this foundation, making collaboration a day-to-day part of how the NIH does business in neuroscience.  By pooling resources and expertise, the Blueprint can take advantage of economies of scale, confront challenges too large for any single Institute, and develop research tools and infrastructure that will serve the entire neuroscience community.
 
FY2005 -- For fiscal year 2005, the Blueprint participants are developing an initial set of initiatives focused on tools, resources, and training that can have a quick and substantial impact because each builds on existing programs.  These initiatives, with the participation of all Blueprint Institutes, include an inventory of neuroscience tools funded by the NIH and other government agencies, enhancement of training in the neurobiology of disease for basic neuroscientists, and expansion of ongoing gene expression database efforts.

NIDCR funded neuroscience researchers will be able to take advantage of the Gene Expression Nervous System Atlas (GENSAT) project since genes important in pain processing in the trigeminal ganglion will be recommended for inclusion in the expansion of this initiative.  Participation in this initiative will help to increase NIDCR grantees’ understanding of the function and regulation of proteins involved in chronic pain disorders.  NIDCR trainees will benefit from supplements to existing training grants that will include course work on Neurobiology of Disease.  The themes of neurodegeneration and neuroplasticity are common to many diseases of the nervous system including chronic pain, which can be considered a neurological disease.

FY2006 -- Advances in the neurosciences and the emergence of powerful new technologies offer many opportunities for Blueprint activities that will enhance the effectiveness and efficiency of neuroscience research.  Blueprint initiatives for fiscal year 2006 will include systematic development of genetically engineered mouse strains of critical importance to research on nervous system and its diseases and training in critical cross cutting areas such as neuroimaging and computational biology.  NIDCR funded neuroscientists will benefit from the cross-Institute training programs in neuroimaging and computational neuroscience.  These areas of emphasis are important to those grantees studying chronic pain conditions and temporomandibular joint disorders.  An expansion of the research cores grant program will allow NIDCR grantees to utilize these facilities and establish collaborative projects with other neuroscientists.  This expansion will also allow for cross-fertilization of research between dental researchers and other institutional departments.  NIDCR neuroscientists will benefit from the Neuromouse Project since genes involved in pain processing will be recommended for inclusion in knock-out studies envisioned for this initiative.

Budget Policy

The Fiscal Year 2006 budget request for the NIDCR is $393,269,000, an increase of $1,440,000 and 0.4 percent over the FY 2005 Appropriation.  Also included in the FY 2006 request, is NIDCR’s support for the trans-NIH Roadmap initiatives, estimated at 0.89% of the FY 2006 budget request.  This Roadmap funding is distributed through the mechanisms of support, consistent with the anticipated funding for the Roadmap initiatives.  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 $308,300 in FY2006.  While no inflationary increases are provided for direct, recurring costs in non-competing RPG's, where the NIDCR has committed to a programmatic increase in an award, such increases will be provided.

Advancement in medical research is dependent on attracting, training, and retaining the best and the brightest individuals to pursue careers in biomedical and behavioral research.  In the FY2006 request, most stipend levels for individuals supported by the Ruth L. Kirschstein National Research Service Awards are maintained at the FY2005 levels.  To help prevent the potential attrition of our next generation of highly trained post-doctoral trainees, stipend levels for post-docs with 1-2 years of experience are increased by 4.0%.  This will bring these stipends closer to the goal NIH established for post-doc stipends in March 2000.  In addition, individual post-doctoral fellows will receive an increase of $500 in their institutional allowance for rising health benefit costs.  The need for increased health benefits is particularly acute for these post-doctoral trainees, who, because of their age and stage of life are more likely to have family responsibilities.  The increases in stipends and health insurance are financed within the FY2006 request by reducing the number of Full-Time Training Positions, because NIH believes that it is important to properly support and adequately compensate those who are participating in these training programs, so that the programs can continue to attract and retain the trainees most likely to pursue careers in biomedical, behavioral and clinical research.

The Fiscal Year 2006 request includes funding for 8 research centers, 118 other research grants, including 16 clinical career awards, and 17 R&D contracts.  Intramural Research receives a 0.3 percent increase and Research Management and Support receives a 0.5 percent increase which is the same as the NIH total increase.  NIDCR is participating in the NIH Neuroscience Blueprint.  The FY2006 request includes $100,000 for a variety of Neuroscience Blueprint initiatives, including neuroscience cores, training initiatives, and the Neuromouse project.”