Dilated cardiornyopathy (DCN4) is a disease characterized by cardiac chamber dilation and deterioration of systolic function. it accounts for 10,000 deaths annually In the United States, and is an etiologically heterogeneous disorder with a strong genetic component. The central goals of this project are to identify genes involved in the pathogenesis of DCM, and to obtain the necessary training in cardiovascular genetics over a proposed five year period, to prepare for a career as an independent investigator. Research will focus on four specific alms critical for identification of genes involved in DCM pathogenesis. 1) Ascertainment and phenotypic characterization of individuals and families with DCM. Families and sporadic cases suitable for genetic analyses will be identified from congestive heart failure and transplant clinics at1he University of Utah and University of Pennsylvania system hospitals. 2) Identification of new DCM loci using genetic linkage analysis in large kindreds. Genome-wide linkage scans using highly polymorphic markers will be performed on large DCM families that do not link to known loci. 3) Positional cloning of a DCM gene on chromosome 3p. The critical genetic interval for a DCM locus previously identified by this laboratory will be cloned. Candidate genes identified in the region will be screened for mutations that co-segregate with the disease phenotype in the family where linkage was established. 4) Identification and mutation screening of candidate genes in familial and sporadic DCM populations. We will identify genes, which on the basis of physiologic rationale, may play central roles in DCM pathogenesis. The candidate genes will be screened for mutations in our patient population. The principle investigator has completed training in clinical cardiology. This application now proposes to build on his research background in Drosophila developmental genetics obtained in the laboratory of Dr. David Hogness. Over a five year period, an expertise in genetic approaches to understanding the molecular pathogenesis of dilated cardlomyopathy will be developed. The candidate's sponsor, Dr. Mark Keating, is a recognized leader in the field of cardiovascular genetics. An advisory committee consisting of two other senior scientists, Dr. Mark Leppert and Dr. Michael Parmacek, will provide additional scientific and career guidance. The Department of Human Genetics at the University of Utah is a center for the study of genetic diseases and provides an outstanding environment for the candidate to develop into an independent investigator.
