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Round 3: 2014-2015 Pilot Projects

Molecular Epidemiology and Natural History of Acadian Usher syndrome

Usher syndrome (Usher), the most frequent genetic cause of deaf-blindness, affects 1 in 20,000 individuals worldwide, but is more frequent in some close-knit communities. Fifteen genes are associated with three clinical subtypes. The USH1C c.216GA mutation accounts for nearly all USH1 cases in the Acadian population of Louisiana. Due to founder effect, the frequency of USH1C appears to be higher in Louisiana, however the real incidence and natural history among our patients is unknown. We created a knock-in mouse containing the Acadian c.216GA mutation, and showed that treatment with antisense oligonucleotides prevents hearing impairment and improves vision when given early in life. Moving this unique therapeutic opportunity into the clinic requires a better understanding of the incidence in Louisiana, and a clear picture of its clinical evlolution. Our goals are to conduct molecular epidemiology studies and develop a clinical natural history of USH1C in Louisiana, necessary for planning clinical trials.

Cardiovascular disease inflammation is due to macrophage associated lipin-1 activity

Cardiovascular disease (CVD) is the number one killer of Louisiana residents, thus new therapeutic options are needed. The underlying cause for almost all catastrophic CVD events is atherosclerosis. Atherosclerosis is a macrophage-mediated chronic inflammatory disorder, thus, inhibition of this inflammation is a potential therapeutic approach to treat CVD. To develop anti-inflammatory therapeutic strategies to treat CVD without making the individual immuno-suppressed we must identify processes that are unique to atherosclerosis. Our work has identified a lipid synthetic enzyme, lipin-1, that uniquely contributes to atherosclerotic macrophage inflammatory responses. Our results suggest this is a targetable process (lipid synthesis by macrophages) that initiates atherosclerotic inflammation. This proposal will elucidate the mechanism by which lipin-1 elicits atherosclerotic inflammation in vitro and test the feasibility of targeting this protein to treat CVD in vivo. As such this proposal is a vital translational step in the development of new therapies to treat individuals with CVD.

Vaccine efficacy in diabetic and elderly patients

Our goal is to determine if an individual's level of inflammation determines their response to vaccination. The aging process and certain diseases, like type-2 diabetes, have been characterized as chronic inflammatory conditions. Affected individuals have higher rates of influenza disease and health care costs; hence, yearly vaccination is recommended. There is a paucity of information comparing vaccination in these high-risk groups and identifying biomarkers that can predict vaccine efficacy. We hypothesize that elderly and diabetic patients have reduced responses to seasonal influenza vaccination that are inversely proportional to their level of chronic inflammation. In this pilot proposal, we will examine adult and elderly diabetic and non-diabetic adults for markers of inflammation and vaccine efficacy before and after influenza vaccination. These studies will help

Endothelial microparticles in COPD: Effect of vascular-targeted therapy

An exciting avenue of drug discovery in COPD revolves around the pulmonary vasculature; changes in the pulmonary vessels/endothelium occur early in the clinical course and may play an active role in the pathogenesis of disease. Biomarkers that may be used to facilitate new treatment strategies are endothelial microparticles (EMPs), submicron vesicles generated from endothelial cell membranes. EMPs may be important in the pathogenesis of COPD, can be used as a biomarker indicating endothelial damage, and may be useful in determining which patients could benefit from vascular-targeted therapy. Our current work suggests that a prostacyclin analog may selectively reduce systemic inflammation by altering the endothelium. EMPs may be exploited to understand the mechanism of benefit of iloprost and to predict which patients will benefit from this therapy. We propose an investigation using blood from patients with COPD receiving iloprost or placebo, as well as in vitro experiments utilizing human endothelial cells.

Testing glial pathways to HAAF in human subjects using 13C magnetic resonance spectroscopy

Hypoglycemia-associated autonomic failure (HAAF) is a condition commonly developed in diabetic patients, which often causes life threatening bouts of hypoglycemia. These hypoglycemic crises are a significant impediment to the maintenance of healthy blood glucose levels in individuals with diabetes. HAAF is thought to be driven by cellular or metabolic adaptations in the brain which alters its response to hypoglycemia. Studies in rodents have demonstrated that dietary restriction can produce alterations in brain metabolism similar to those associated with HAAF. Therefore, we hypothesize that HAAF may be driven by metabolic adaptations in the brain, normally induced by prolonged starvation, which are triggered in diabetic individuals by treatment induced exposure to hypoglycemia. The primary goal of our LA CaTS pilot project is to conduct a prospective observational study in humans to test the hypothesis that prolonged fasting will cause alterations in brain metabolism similar to those observed in individuals with HAAF. 

Detection of Hereditary Colorectal Cancer Mutations in Cajuns

Cajuns are the majority of the white population in the Acadian region of south Louisiana. We have recently uncovered that colorectal cancer (CRC) prevalence in whites in the Acadian parishes are disproportionately higher than the rest of the state and are among the highest in the U.S. Furthermore, CRC is developing at a young age in the region. Since the Cajuns are a known founder population for multiple genetic diseases, it is likely that these high CRC rates are due to a founder mutation in for hereditary CRC, like Lynch syndrome (LS). In order to analyze this further, we will test CRC samples from these young Cajuns for microsatellite instability, a hallmark of LS. Our project will address an important public health concern since early intervention can effectively decrease CRC incidence and mortality.

Plaque destabilization via shear stress and vascular strain induced changes in non-coding RNA

Our limited understanding of the mechanisms behind plaque rupture is a critical barrier to developing methodologies for prevention of myocardial infarction and stroke. Our lab has found the expression of two microRNAs and a related circular RNA are altered in plaques post-rupture and in relation to shear stress. We hypothesize that increased shear stress and vascular strain alters non-coding RNA (ncRNA) expression to promote plaque destabilization. We will test this via two aims. Aim 1 will identify ncRNAs associated with plaque rupture using next generation sequencing and relate their expression to shear stress and vascular strain using computational modeling. Aim 2 will use custom-designed bioreactors to demonstrate in vitro that increases in laminar shear stress and in vascular strain reduce proliferation and increase apoptosis in vascular smooth muscle cells through changes in ncRNA expression. This project thus combines an innovative approach to studying plaque rupture with cutting edge methodology to determine the role of flow and strain mediated changes in ncRNA in plaque destabilization.