Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare human disease with characteristics of premature aging that include loss of subcutaneous fat, wrinkled skin, loss of hair, arteriosclerosis, and difficulty in moving joints. About 90% of progeria patients die at an early age from progressive arteriosclerosis. HGPS is caused by mutations in human lamin A (hLA), a protein component of the nuclear lamina. The long-term objective of the proposed research is to determine the molecular basis by which mutations in the hLA gene alter nuclear function to cause these premature aging defects. It is our hypothesis that nucleoplasmic lamin structures, in addition to those in the lamina, form a nucleoskeletal system that provides the infrastructure required for crucial nuclear functions, including DNA replication, transcription, chromatin organization, nucleocytoplasmic transport and nuclear disassembly, assembly and shape. Understanding how these functions are altered by HGPS mutations will shed light on the mechanisms responsible for the multiple age-related disorders seen in patients with progeria, including cardiomyopathies and strokes. To this end, two laboratories with considerable expertise in lamin genetics, structure, function and nuclear transport will collaborate to address the following specific aims: 1) Characterize the effects of HGPS hLA mutations on nuclear structure and organization by the coordinated use of biochemical and microscopic methods. 2) Characterize the effects of HGPS hLA mutations on nuclear functions: DNA replication and cell division using HGPS patient cells and cell-free preparations of Xenopus nuclei. 3) Characterize the effects of HGPS hLA mutations on nuclear functions: nuclear import and export, nuclear pore complex structure and nuclear envelope permeability. 4) The use of human and animal cell models to test the effects of hLA mutations on mesenchymal cell types most affected in HGPS. These collective studies will provide important insights into how hLA mutations cause the defects seen in progeria.
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