Defining the roles of NOTCH1 in first heart field development using 2D and 3D chamber-specific human ipsc models

Active Project Grant Awarded Last action

Award ID
F31HL188979
Recipient
Awarding agency
Obligated
$45,514

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Place of performance
Columbus, OH 43205, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Hypoplastic left heart syndrome (HLHS) is a rare congenital heart disease characterized by underdeveloped left sided heart structures, specifically the left ventricle. Due to the underdeveloped ventricle, the heart cannot effectively pump blood to the body, so patients usually require surgical intervention or transplant within the first few weeks of life. The NOTCH1 gene is believed to play a role in first heart field development, which gives rise to the left ventricle, influencing cardiac cell fate determination, cardiomyocyte differentiation, and myocardial compaction. Variants in NOTCH1 are commonly linked to HLHS, so understanding how the gene contributes to LV hypoplasia is vital. However, previous studies exploring this connection fail to recapitulate human structural and genetic complexities of the human heart. In this project, we aim to generate two and three-dimensional cardiac models to study the role of NOTCH1 in cardiac cell processes during first heart field development and the functional consequences caused by NOTCH1 deficiency. Our central hypothesis is that NOTCH1 is crucial in first heart field development, specifically in cardiac chamber and layer formation via impaired cardiac differentiation. A deficiency in NOTCH1 will cause impaired cardiac differentiation and proliferation, resulting in an underdeveloped left ventricle and disrupted cardiac performance. Using crispr-edited NOTCH1-knockout human induced pluripotent stem cell lines, we will generate left ventricle-like cardioids and cardiomyocytes and perform electrophysiology techniques, such as patch clamp to assess cardiomyocyte function. We will also perform single cell RNA-sequencing, proliferation assays, as well as monitor cardioid structure development, including cavity size and formation, and myocardial, endocardial, and epicardial layer growth over the course of development. Using this data, we will elucidate the role of NOTCH1 in cardiac differentiation and ventricular development and how IT contributes to pathogenesis of HLHS.

Quick answers

Who received award F31HL188979?

F31HL188979 was awarded to Research Institute At Nationwide Children's Hospital by National Heart Lung and Blood Institute (National Institutes of Health) on February 6, 2027.

How much is award F31HL188979 worth?

$45,514 has been obligated on F31HL188979.

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