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Record Count: 5
To sort columns alphabetically or numerically, click on the column
header (Title, Principal Investigator, Institution, City, ST, Award Code, or
Pubs).
DESCRIPTION (provided by applicant):
The human genome contains numerous endogenous retroviral (HERV) elements. Expression of these elements is associated with cancer, autoimmunity, impaired placental development, and recombination events that impair genomic stability. Epigenetic events such as DNA methylation and histone modifications play crucial roles in repressing transcription of HERV elements. Recently, a novel modification of histones that is mediated by holocarboxylase synthetase (HCS) has been identified: binding of the vitamin biotin to distinct lysine residues in histones H2A, H3, and H4. Specifically, it has been demonstrated here that K8- biotinylated H4 (K8Bio H4) and K12-biotinylated H4 (K12Bio H4) are associated with gene silencing and heterochromatin structures. Importantly, the abundance of biotinylated histones depends on dietary biotin supply. Arguably, diet is an environmental factor that can be easily manipulated to affect epigenetic events that promote human health. The long-term objective is to identify epigenetic mechanisms through which changes in the dietary uptake of biotin alter expression of HERV. The specific aims are to test the hypothesis that: 1) K8Bio H4 and K12Bio H4 co-localize with methylated DNA at HERV promoter sequences in the human genome. Further, this aim will test the hypothesis that knockdown of HCS is associated with decreased biotinylation of histones, mediating de-repression of viral elements; and 2) Dietary biotin deficiency decreases the abundance of K8Bio H4 and K12Bio H4 at HERV promoter loci. Studies with this aim will test the idea that biotin deficiency is associated de-repression of HERV elements, promoting abnormal growth, transformation, and genomic instability in human cells. Both biotin deficiency and supplementation are fairly common in the U.S. The research proposed here investigates a novel and unique mechanism by which dietary supply of the vitamin biotin modulates epigenetic events that are crucial for HERV silencing. These studies are likely to identify means by which manipulation of the environmental factor "diet" increases genomic stability and decreases cancer risk.
DESCRIPTION (provided by applicant): Fumonisin B1 (FB1) is a mycotoxin commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of FB1-contaminated corn and increased neural tube defect rates has been observed in human populations relying primarily on corn as their dietary staple. FB1 disrupts sphingolipid biosynthesis by inhibiting ceramide synthase, resulting in elevations in sphingoid base-1-phophates, and diacylglycerolphosphoethanolamine lipids. All of these compounds are candidate ligands for the MHC-like molecule CD1d that functions in immune surveillance and the presentation of lipid antigens to the invariant 12 T-cell receptor on natural killer T-cells (NKT). Activated NKT cells can produce either a Th1 or a Th2 cytokine repertoire, depending on the nature of the ligand. Exposure to the FB1 mycotoxin elicits an immune response that involves the production of Th1 cytokines (IFN3 and TNF1). We hypothesize that the lipid compounds that accumulate after FB1 exposure are recognized by CD1d and presented to NKT cells as foreign antigens that elicit a Th1 cytokine response. Elevated Th1 cytokines during pregnancy often result in abortion, and in most species examined, gestational exposure to FB1 results in an increased incidence of fetal resorptions. However, in the inbred LM/Bc mouse strain, exposure of pregnant dams to FB1 results in a high incidence of fetal malformations. The LM/Bc mouse has an altered innate immune response, and deficiencies in uterine natural killer cells (uNK). CD1d is found on fetal trophoblast cells, and NKT and uNK are found in the placenta at the maternal-fetal interface. Stimulated NKT cells can transactivate uNK to produce Th1 cytokines. Using unique inbred and mutant mouse models, we will test the hypothesis that FB1 exposure in immunocompetent animals results in a CD1d-NKT uNK-mediated Th1 response that results in trophoblast cell death and pregnancy termination, while maternal immunodeficiencies in this pathway allow the pregnancy to continue to term, increasing the risk for teratogen-induced malformations. The objectives of this proposal are to determine the factors that confer increased susceptibility to fetal malformations following maternal FB1 exposure, and decipher the CD1d NKT cell sphingolipid- immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome. The use of FB1 as a model teratogen will also facilitate our understanding of the mechanisms through which maternal immunodeficiencies may contribute to adverse pregnancy outcomes following exposure to other environmental toxicants. It has been shown that NKT cell deficiencies result in autoimmune disorders such as diabetes, and that the offspring of diabetic mothers are at increased risk for fetal malformations. The proposed studies are therefore expected to open new avenues for investigating the role of alterations in lipid metabolism, maternal immunity, and Th1/Th2 cytokine profiles at the maternal-fetal interface as contributing factors in diabetic embryopathies. PUBLIC HEALTH RELEVANCE: Fumonisin B1 is a mycotoxin produced by a fungus commonly found on corn that has recently been implicated in developmental toxicity. An association between maternal consumption of fumonisin-contaminated corn and increased risk for offspring with birth defects has been observed in human populations relying primarily on corn as their dietary staple. We hypothesize that maternal immunodeficiencies play a role in susceptibility to fetal malformations following gestational exposure to fumonisin. The objectives of this proposal are to determine the factors that contribute to increased susceptibility by deciphering the sphingolipid-immune system interactions at the maternal-fetal interface that play a critical role in determining pregnancy outcome.
DESCRIPTION (provided by applicant): Exposure to the ultraviolet (UV) component of sunlight is the major cause of nonmelanoma skin cancer, the most common form of cancer in the United States. Despite its significance for human health, however, the mechanisms through which UV causes cancer are not well understood. One potential mechanism for skin carcinogenesis involves the UV-induced activation of Erbb2, a proto-oncogene and orphan receptor tyrosine kinase. Our preliminary data reveal novel mechanisms through which Erbb2 contributes to skin carcinogenesis at multiple stages, both during tumor development and progression. Our central hypotheses are 1) that Erbb2 promotes cell cycle progression and thus increases UV-induced skin carcinogenesis by dampening DNA damage response checkpoints and 2) that Erbb2's suppression of proteinase inhibitor Thrombospondin 1 and its upregulation of matrix metalloproteinases stimulate keratinocyte invasion and angiogenesis, leading to malignant progression. The long-term objective of this application is to understand the biological functions of Erbb2 during carcinogenesis and the mechanisms through which Erbb2 acts. Studies are proposed to reveal the biological significance of Erbb2 in skin tumor development and progression, to determine the molecular mechanisms by which Erbb2 regulates cell cycle progression and a DNA damage checkpoint through Cdc25a, and to determine how Erbb2 causes skin cancer progression. These studies will use models that we have developed for both the inhibition and genetic ablation of Erbb2 in the skin. Upon completion, these studies will reveal the basic mechanisms of cell cycle regulation and checkpoint control following UV exposure as well as novel mechanisms through which Erbb2 regulates cell cycle arrest after DNA damage and promotes malignant progression. This research will provide a comprehensive analysis of the importance of Erbb2 in skin carcinogenesis, will elucidate novel mechanisms through which Erbb2 acts, and will provide new targets for therapeutic intervention during skin carcinogenesis.
Ultraviolet irradiation is the cause of most of the more than one million skin cancers diagnosed in the United States each year. The proposed research will reveal basic molecular mechanisms responsible for the induction of skin cancer in response to ultraviolet irradiation. Successful completion of the proposed research will allow for the development of novel therapies designed to treat or prevent skin cancer.
DESCRIPTION (provided by applicant): COPD is currently the fourth leading cause of death. It is a complex condition characterized by progressive airflow limitation resulting from emphysema and airway disease. Cigarette smoking is the major cause, but 20% of cases develop in non-smokers and smokers have varying degrees of susceptibility. Emphysema, which is characterized by lung tissue destruction, is thought to result from injury caused by smoke. Tissue destruction, however, represents an imbalance between tissue injury and the capacity of tissues to repair. Recent evidence suggests that early life events can contribute to COPD risk. Among these, exposure to cigarette smoke has been demonstrated to be a risk factor, and evidence supports the concept that maternal environmental smoke exposure is sufficient. The current proposal will test the hypothesis that fetal exposure as a result of maternal environmental smoke exposure leads to a defect in the maintenance of stem/precursor cells in the lung. As a result, the lung is unable to maintain repair functions with age and, as such, is predisposed to develop senile emphysema. This increased susceptibility to develop emphysema is exacerbated by exposure to smoke-induced injury in adulthood. This hypothesis will be tested by exposing pregnant mice to levels of smoke consistent with environmental exposures. Pups will then be monitored for lung cell repair functions and susceptibility to develop emphysema as they age. The role of stem cells will be evaluated by quantifying progenitor stem/cell functions in the exposed animals using in vivo and in vitro methods. Bone marrow (stem cell) transplants will be used to confirm the role of stem cells and to attempt to restore lung function. This will establish fetal environmental smoke exposure as a cause of adult COPD and provide a novel basis for therapy.
DESCRIPTION (provided by applicant)
Organic dust exposure is an important occupational hazard for persons who work in swine confinement
barns. Organic dust exposure to naive individuals results in an intense systemic and pulmonary
inflammatory response that attenuates over time, suggestive of immunologic adaptation. However, despite evidence for adaptation to the exposure, one-third of all workers develop chronic lung disease. This important observation suggests that repeat organic dust exposure modulates the immune system response. Numerous studies have characterized the inflammatory response to a single organic dust exposure, but there have been few studies characterizing the response to repeat exposures. Utilizing a newly developed murine model, the investigators have demonstrated that mice adapt to repeat swine facility organic dust exposure, yet manifest evidence of lung tissue inflammation. This led them to explore the innate immune inflammatory response to repeat versus single organic dust exposure.
In human monocytes, the investigators found that a unique inflammatory response occurs to repeat swine facility organic dust exposure as compared to a single exposure, which is independent of endotoxin. Repeat exposure to swine facility dust results in diminished tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1-beta, but persistently elevated IL-8 and IL-10 compared to a single dust challenge in human monocytes. Elevated IL-10 suppresses pro-inflammatory cytokines, but has also been associated with mucus metaplasia and lung tissue inflammation in mice. Preliminary data also suggest that the inflammatory response to organic dust may be mediated through protein kinase C (PKC) activity. Based on these novel observations, the investigators hypothesize that chronic innate immune inflammatory adaptation responses occur with repeat organic dust exposure. To test this hypothesis, they will perform experiments outlined in three specific aims. In aim 1, the investigators will characterize and establish the inflammatory mediators involved with repeat versus single organic dust exposure in human monocytes. In aim 2, they will determine the mechanisms of repeat versus single organic dust-induced inflammation focusing on the key role of PKC activation. In aim 3, the investigators will determine the role of specific inflammatory mediators and PKC activation using an in vivo model of repeat versus single organic dust exposure in mice.
Finally, the candidate is an adult allergist and immunologist with an interest in organic dust-induced
diseases. She is a well-supported candidate with a long-standing interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award.
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