Congenital heart disease is the leading cause of infant mortality and morbidity in the developed world. The outflow vasculature of the heart is composed of aorta, pulmonary artery and a system of aortic arch arteries (AAAs) - proper development of this system is essential for the separation of venous and oxygenated blood and is required for human viability and health. Abnormal patterning of aortic arch arteries gives rise to severe birth defects and often occurs as a part of other congenital syndromes such as DiGeorge syndrome, one of the most common chromosome microdeletion syndromes in humans (1 in 4000 live births). Our long-term goal is to understand molecular and genetic pathways mediating normal AAA development in order to gain insight into the processes that go awry during pathological morphogenesis of the AAAs. Experiments in my laboratory led to the discovery that expression of integrin a5 in Isl1-positive cells and their descendants is required for the development of the aortic arch. We also found that integrin a5 is required for the presence of normal numbers of cardiac neural crest (CNC) cells in the pharyngeal arches. Since CNC cells give rise to vascular smooth muscle cells (VSMCs) of the AAAs and since normal formation, recruitment and association of VSMCs with aortic arch artery endothelial cells is required for the proper patterning of the AAAs, we propose to find out the role of integrin a5 in the development of the CNC cells and its descendants, VSMCs.
Our specific aims will address three important questions about the function of integrin a5: a) what is the general role of integrin a5 in CNC development;b) how does the expression of integrin a5 in non-CNC cells affect the development of CNC and its derivatives;c) is integrin a5 required to facilitate growth factor signaling in the relevant pharyngeal arch cell types. To address these questions we propose the following three specific aims: I) To test the hypothesis that Itga5 is required to regulate survival and proliferation of the CNC progenitors;II) To test the hypothesis that expression of Itga5 in non-CNC cells is required for the formation and/or remodeling of AAAs;III) To determine the cellular and molecular mechanisms of Itga5 function during AAA development. Upon completion of this project, we will gain a significant insight into the function of integrin a5 in AAA development and into the normal process of AAA morphogenesis.

Public Health Relevance

. Aortic arch arteries rout the blood from the heart into the pulmonary and systemic circulation and their proper development is essential for the separation of venous and oxygenated blood, which is required for human viability and health. Abnormal patterning of aortic arch arteries gives rise to severe birth defects and often occurs as a part of other congenital syndromes such as DiGeorge syndrome, one of the most common chromosome microdeletion syndromes in humans (1 in 4000 live births). Elucidation of molecular and genetic pathways required for normal aortic arch artery development is required to understand the processes that go awry during abnormal development of the aortic arch arteries. We discovered that the expression of integrin a5 in Isl1-positive cells and their descendants is required for the development of the aortic arch. Our experiments also indicate that the function of integrin a5 is necessary for the presence of normal numbers of cardiac neural crest cells - these cells will give rise to the vascular smooth muscle cells of aortic arch arteries and are required for the formation and patterning of these vessels. Our proposed studies will determine in which cell type the expression of integrin a5 is necessary for aortic arch development and potential mechanisms downstream of integrin a5. These studies will provide important insight into the molecular and genetic pathways that play a requisite role during aortic arch artery development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL103920-05
Application #
8469563
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$365,211
Indirect Cost
$129,591
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Liang, Dong; Wang, Xia; Mittal, Ashok et al. (2014) Mesodermal expression of integrin ?5?1 regulates neural crest development and cardiovascular morphogenesis. Dev Biol 395:232-44
Mittal, Ashok; Pulina, Maria; Hou, Shuan-Yu et al. (2013) Fibronectin and integrin alpha 5 play requisite roles in cardiac morphogenesis. Dev Biol 381:73-82
Pulina, Maria V; Hou, Shuan-Yu; Mittal, Ashok et al. (2011) Essential roles of fibronectin in the development of the left-right embryonic body plan. Dev Biol 354:208-20