Decorin Deficiency in Hutchinson-Gilford Progeria

Tufts University Boston, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare "premature aging" syndrome of unknown etiology which is characterized by sclerodermatous skin changes, skeletal deformities, and severe global premature atherosclerosis. Extracellular matrix molecules play integral roles in all of the systems affected by HGPS. Published data and preliminary data from this laboratory have provided evidence for dramatically decreased production of decorin by HGPS and other progeroid fibroblasts. Decorin is an extracellular matrix proteoglycan involved structurally and in cell signaling in skin, blood vessels, skeletal and many other tissues. We will investigate the role of decorin as a potentially pivotal molecule for the HGPS disease phenotype. We will assess the consistency of this molecule as a disease marker by measuring all the available HGPS fibroblast lines, including parental fibroblasts, for decorin deficiency compared to age matched controls. We will begin to determine whether the decorin deficiency originates at the transcriptional or translational level using Northern and Western blot analysis, respectively. We will also determine whether HGPS fibroblasts have a more generalized defect in the ability to synthesize proteoglycans. For this analysis, total radio labeled proteoglycans from the media and cell layers of normal and HGPS fibroblasts will be 1) examined by SDS-PAGE gels and 2) quantitated by gel exclusion chromatography, before and after digestion with enzymes to remove their glycosaminoglycan chains. Finally, we will increase decorin expression experimentally in HGPS cells and determine whether various characteristic of the HGPS fibroblast phenotype are corrected. These studies should help: 1) identify targets for clinical manipulation, 2) find clues to the genetic defect by `backtracking' from our findings; and 3) further define a molecular phenotype for research studies and as a diagnostic tool.