# The Six-Family Genes in Cardiovascular Development And Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $295,318

## Abstract

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 Building on the published and our unpublished findings, we propose to pursue a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.

## Key facts

- **NIH application ID:** 9889166
- **Project number:** 5R01HL136921-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Xue Sean Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $295,318
- **Award type:** 5
- **Project period:** 2017-04-01 → 2020-09-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889166

## Citation

> US National Institutes of Health, RePORTER application 9889166, The Six-Family Genes in Cardiovascular Development And Disease (5R01HL136921-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889166. Licensed CC0.

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