The objective of this proposal is to identify causal genetic defects in patient-specific congenital heart disease (CHD) with the aim of providing specific genetic information and underlying mechanism for future targeted intervention by personalized treatment of CHD patients, an essential component of the `bedside-to-bench-to-bedside' concept in congenital and other heart disease treatments. We propose two complementary approaches: (1) gene discovery based on cardioblast expression profiles from wildtype and mutant Drosophila hearts with subsequent functional testing and integration into a genetic regulatory network of cardiogenesis that will link core cardiac transcription factors to heart morphogenesis; (2) genetic modeling of CHD gene candidates, identified from 2 cohorts of patient-derived genomic and transcriptome sequencing data, using our Drosophila heart model. Cohorts include one with copy number variations (CNV) and another based on genes' mutation frequency from patients with Tetralogy of Fallot (TOF). Initial new CHD gene discoveries will immediately be be integrated into known pathways, such as genetic interactions with tinman/NKX2-5, or be categorized as `new' for further testing and network integration.
Aim 1 is to continue the construction of a gene network of cardiac morphogenesis based on gene discovery in Drosophila, whereas Aim 2 is to identify new causal CHD genes and their mechanisms. Our goal is not to approximate a specific CHD phenotype in the fly, but rather (a) to harness the power of the Drosophila heart model we have created, where gene discovery and testing for interactions between multiple genes can be achieved efficiently, and (b) to identify conserved genes and pathways that are relevant to CHD.

Public Health Relevance

Congenital heart defects are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns, underscoring the importance of studying the underlying causes, the vast majority of which are still unknown. Unraveling the genetic causes and mechanisms of congenital heart diseases via our Drosophila heart model is expected directly impact patients' treatment options.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054732-22
Application #
9511870
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
1995-08-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sanford Burnham Prebys Medical Discovery Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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