The Mitochondrial Citrate Carrier as a Novel Player in Congenital Heart Disease
Abstract
The proposed research addresses the Fiscal Year 2021 Peer Reviewed Medical Research Program Topic Area of Congenital Heart Disease. The areas of encouragement this proposal relates to are: research to design and implement improved or novel models and research to improve the understanding of the causes of congenital heart defects. Congenital heart disease (CHD) refers to structural and functional defects of the heart that are present at birth. CHD is the most common type of birth defect and affects 1% of U.S. births per year. These conditions commonly require surgical intervention and lifelong medical treatments, which can have significant impacts on individuals, families, and caregivers. Yet, while we know of several genetic risk factors for CHD, there is almost nothing that can be done to prevent them from developing. Work to expand our knowledge of what causes CHD is needed to inform new approaches to prevention and screening. The proposed research will study a new mouse model that exhibits CHD to uncover how CHD arises in the context of 22q11.2 deletion syndrome (22q11DS, or DiGeorge syndrome). 22q11DS results when a piece of the genetic material of chromosome 22 is missing, which causes a multisystem disorder that affects development of the heart, brain, and other organs and structures. CHD in 22q11DS has long been thought to arise in large part from the loss of a gene called TBX1. However, this new mouse model is missing one or two copies of a different gene, Slc25a1, that is affected by 22q11.2 deletion, and these mice develop CHD like those seen in 22q11DS. This surprising finding implicates a new genetic factor in CHD. We propose to determine if Slc25a1 alone causes the CHD occurring in 22q11DS, or if it works together with Tbx1 to produce the full range of heart defects that occur in 22q11DS. This work will reveal a new factor that controls how the heart develops and will uncover potential interactions between genetic pathways that may extend beyond 22q11DS to other instances of CHD. In addition, Slc25a1 produces a protein that transports a nutrient called citrate. When SLC25A1 is missing, like in the new mouse model and in 22q11DS, it is likely that citrate is not getting to the right place or in the right amount. However, citrate can be obtained from the diet and through food or existing dietary supplements. Much like supplementation with folic acid during pregnancy successfully overcomes a cellular deficit to prevent neural tube defects, we propose that citrate supplementation during pregnancy could reduce or prevent CHD due to SLC25A1 defects or in 22q11DS. We will provide supplemental citrate to pregnant mice whose embryos are missing only Slc25a1 or are also missing the larger segment of genes involved in 22q11DS to determine how restoring the citrate supply in cells influences (lessens) the development of CHD. Together, this discovery work could produce a big leap forward by identifying new genetic pathways to understand how CHD arises, which will be essential for improved genetic screening, and by informing clinical development of an accessible, inexpensive therapeutic strategy for CHD prevention—prenatal citrate supplementation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210073
Entities
People
- Jennifer Kwong
Organizations
- Emory University
- United States Army