}: The proposed research is geared to a near-complete elucidation of the genes, their sequence variants and their biochemical pathways that are mutant and dysregulated In Hirschsprung disease (HSCR); the 'HSCR gene universe.' HSCR is a common neuro-deveiopmental congenital disorder associated with the lack of intramural ganglia along varying lengths of the gastrointestinal tract. The overall goal Is to identify the critical rate-limiting steps in the development of the enteric nervous system (ENS) In humans so that the disease process can be elucidated and, consequently, precise targets for future therapeutic intervention can be. identified. Past research, supported by this grant, has already identified many key molecular genetic features of HSCR. To accomplish the major goals the following aims are being pursued In the next phase: (I) Quantify the mutational burden and effects at the three major signaling pathways (RET, EDNRB, SEMA3) deficient in HSCR; (II) Define the extent, Impact and molecular consequences of large copy number variants In HSCR; (III) Quantify the r6le and impact of common and rare sequence variants in HSCR; (iV) Expand on an existing patient/family collection and maintain a current Information resource for researchers and patients. The general approach being taken Is to use state-of-the-art technologies to screen the genome of HSCR patients, their affected relatives and their parents, using DNA and RNA analyses followed by computational studies, to Identify genes, variants and molecular pathways dysregulated In HSCR. The putative candidate genes are then studied in greater detail in mouse, zebrafish and cell culture models to demonstrate that they indeed contribute to aganglionosis and con-espond to critical rate-limiting steps of the disease. To accomplish these aims, we will also Increase patient and family recruitment from a variety of sources and disseminate our research results in a manner suitable for both the research and HSCR patient communities.
Hirschsprung (HSCR) is a common neuro-deveiopmental congenital defect and a model for understanding the role of multiple genes and pathways In complex human disease. Our goals are to provide a near complete moiecijlar description of genes, sequence variants and molecular processes disrupted in HSCR using genomics approaches. Our genetic discoveries will specify those critical, rate-limiting molecular processes in this disorder where genetic therapies can be targeted to reduce recurrence risk in families.
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