Congenital heart disease is the number one cause of birth defects. Nearly 1/3 of the affected patients have outflow tract (OFT) anomalies indicating that OFT formation is particularly prone to error. Many of the affected patients won't live past their first year birthday. Despite the significant recent advances in understanding the molecular basis of OFT formation, the central question regarding the embryonic origins of OFT remains to be defined. For example, it is still unclear whether the intrapericardial arterial trunks, i.e., the aortic and pulmonary trunks, originate from the common or different pools of progenitors. Answer to the question is critical to understanding the morphogenetic process separating the systemic and pulmonary circulations and, the pathological process leading to the OFT anomalies. The popular belief is that the aortic and pulmonary trunks are derivatives of conotruncus - a transient embryonic structure, and from the common pool of progenitors. However, results from our own studies and others suggest otherwise. Building on the published and our unpublished findings, we propose to pursue a novel concept by testing the hypothesis that the arterial trunks are de novo structures that originate from different pools of progenitors; timely deployment of these progenitors, orchestrated by a Six- dependent transcriptional program, is central to OFT development and pathogenesis of polygenic CHDs. We have designed three specific aims: 1) to examine whether the aortic and pulmonary trunks are intrinsically different, and are coordinately added to the heart; 2) to examine whether OFT formation depends on the timely deployment of progenitors orchestrated by the Six-family transcription factors; 3) to examine whether Six-family transcription factors are genetic modifiers of chromosome 22q11.2 deletion syndrome (22q11.2DS) or DiGeorge syndrome. 22q11.2DS is the most common chromosome microdeletion syndrome with a wide spectrum of OFT defects ranging from the interruptive aortic arch to tetralogy of Fallot to common arterial trunk. Patients with 22q11.2DS often require complex reconstructive surgeries and lifelong specialized cares thereafter. Successful completion of the proposed research is expected to challenge the current dogma that the arterial trunks are derivatives of the preexisting structure and, moreover, provide a new conceptual framework to understand cardiac OFT development and pathogenesis of CHD.

Public Health Relevance

Congenital heart defect affects 19-75 per 1,000 live births, and many of them won't live past their one-year birthday. These who survived to adulthood often require lifelong specialized care. Anultimategoaloftheproposalistoadvanceourunderstandingofcardiacbirthdefect,andto amelioratequalityoflifeoftheaffectedpatientsandfamilies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL136921-01
Application #
9289416
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2017-04-01
Project End
2021-02-28
Budget Start
2017-04-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115