This project will investigate basic mechanisms of Primary Pulmonary Hypertension (PPH), a lethal disease which causes progressive obstruction of small pulmonary arteries. The first component of this study is to establish a natiOnal registry of familial PPH (FPPH). The primary goal of the family registry is to establish and expand the database of FPPH pedigrees to definitively establish the mode of inheritance of FPPH, which our initial segregation analysis suggests is autosomal dominant. The FPPH family registry will provide the framework for the linkage analysis of the molecular search for basic mechanisms of PPH. We will develop a tissue bank for specimens (DNA & transformed lymphocytes) from families and patients with pulmonary hypertension, both for our investigations locally and to be a national resource for other interested investigators. Our search will use three different approaches to investigate for a FPPH gene locus. First, we will perform karyotyping and high resolution chromosome studies to search for a chromosomal translocation, interstitial deletion, or inversion, the finding of which would implicate a specific gene locus. Second, we will pursue the proposed association of human leukocyte antigen (HLA) tissue type with familial PPH in a parallel attempt to identify a related locus about which to perform an intensified molecular search, using regional mapping studies of closely linked markers. Finally, we will perform linkage analysis in selected PPH families which have the most informative inheritance patterns, using PCR based microsatellite markers for selected candidate genes, including those for transforming growth factor beta, endothelin, beta globin, and HLA. An additional promising approach will include a search for linkage of FPPH to genes with GC-rich trinucleotide repeats, as has recently been successful for other diseases with genetic anticipation, including Fragile X syndrome, myotonic dystrophy, and Huntington's disease. This is a vitally important proposal, we know of no other projects designed to search for the basic molecular mechanism of Primary Pulmonary Hypertension, a critically important disease.
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