Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian cause of adult end-stage renal disease and accounts for 10% of patients on renal replacement therapy. ADPKD manifests itself in the proliferation of bilateral fluid-filled renal cysts, as well as in cardiovascular phenotypes such as intracranial an aortic aneurysms. ADPKD is caused by loss-of- function mutations in the PKD1 and PKD2 genes, which code for the proteins polycystin-1 (pc1) and polycystin-2 (pc2), respectively. Despite the advances made in the ADPKD field since the initial cloning of these genes in the 1990's, the molecular basis for ADPKD-associated aneurysm remains poorly understood. This research proposal seeks to better understand the molecular abnormalities in ADPKD that lead to aneurysm. The hypothesis that motivates project is that genes and pathways that are dysregulated in other hereditary aneurysm syndromes may also underlie the aneurysm phenotype of ADPKD. To investigate this hypothesis, this project will focus on four candidate pathways that have been demonstrated to confer increased risk for aneurysm development: transforming growth factor ? (TGF-?) signaling, cell-cell communication signaling through the Notch1 receptor, the transcription factor SRY box 17 (SOX17) pathway and the collagen-crosslinking enzyme lysyl oxidase (LOX). The hypothesis will be tested by investigation of the following two specific aims.
The first aim i s to determine the extent of dysregulation of these fou aneurysmogenic pathways in cell and animal models of ADPKD. The investigators have preliminary data to support dysregulation of LOX expression in cellular models of ADPKD, and evidence from the literature suggests that the other three pathways may also be perturbed in the context of ADPKD.
The second aim i s to determine the mechanisms that underlie pc1- and pc2-mediated regulation of these aneurysmogenic pathways. Given the importance of the polycystin proteins in direct and indirect regulation of gene expression, it is possible that pc1 and pc2 exert their effects on these pathways at the level of gene transcription; however, effects upstream or downstream of gene transcription cannot be excluded and thus will also be investigated. This research may provide insights not only into pathways that lead to aneurysm development in ADPKD, but also into pathways that lead to renal cystogenesis in ADPKD. Training Plan: The proposed activities under this fellowship will provide the applicant with strong research, clinical and academic training that will prepare her for a career as an independent physician-scientist, with a focus on conducting research in an area of unmet clinical need.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of adult end-stage kidney disease and affects 600,000 Americans. In addition to kidney disease, up to 20% of ADPKD patients suffer from brain aneurysms, and rupture of these aneurysms carries a 60% mortality rate. We seek to better understand the mechanisms behind aneurysm formation in ADPKD, with the hope of laying the foundation for future development of screening blood tests and preventative treatments that can be used in the management of ADPKD patients in the clinic.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F10A-S (20)L)
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Meadows, Tawanna
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Yale University
Other Domestic Higher Education
New Haven
United States
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