THOMAS JEFFERSON UNIVERSITY
Grant: $403,927 - National Institutes of Health - Sep. 21, 2009
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Award Description: HS chains regulate key physiologic processes and do so by various mechanisms and most notably by restricting the topographical distribution of signaling factors within tissues, but it is not known whether defects in such signal-restriction mechanisms subtend HME. In Preliminary Studies using mouse mutants expressing low HS-PGs (perlecan and syndecans), we found that a key growth plate signaling factor -Indian hedgehog- was widely and abnormally distributed within growth plate and adjacent perichondrium, and this was followed by exostosis formation. In additional Preliminary Studies, we created Ext mutant mice that develop exostoses in long bones and ribs and that are the first genuine model of human HME. Using these novel findings and innovative animal models, we propose to identify and test mechanisms of HME pathogenesis. Our central hypothesis is that deficiency in HS production causes leakage of chondrogenic factors (most notably Indian hedgehog) from upper growth plate zones into adjacent perichondrium, altering the developmental program of perichondrium-associated progenitor cells and inciting ectopic chondrogenesis and exostosis formation (Aim 1). We will then test whether exostosis formation can be prevented by pharmacologic interference with hedgehog signaling and associated transcriptional chondrogenic switches (Aim 2). This Challenge Grant will jump-start mechanistic research on HME pathogenesis by exploiting our novel mouse models of this neglected, painful and debilitating human disorder, will identify molecular targets of intervention, and will test a specific therapeutic strategy to prevent exostosis formation. The number of HME patients is small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this neglected disease will actively be studied and a cure may one day be found.
Project Description: As described in Award Description.
Jobs Summary: No jobs created or retained yet as project has not started. (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 21, 2009. Help expand these official descriptions using the wiki below.
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