Mohamad Azhar

Assistant Research Professor, Retired
Institution
University of Arizona
Tucson
Arizona
Current Research: 

My research investigates the role of Transforming Growth Factor beta (TGFbeta) signaling in cardiovascular development and pathogenesis of aortic aneurysm.  My research is currently supported by grants from Arizona Biomedical Research Commission (ABRC) (Azhar, PI), The Steven M. Gootter Foundation (Azhar, PI), The Stephen Michael Schneider Investigator Award for Pediatric Cardiovascular Research and The William J. “Billy” Gieszl Endowment for Heart Research (Azhar, PI), and The National Heart, Lung and Blood Institute (Azhar, Co-Investigator).

We use mouse genetic engineering, molecular, cellular and developmental biology techniques, and state-of-the-art biomedical imaging (intravital multi-photon imaging) and biomechanical approaches to analyze the cardiovascular phenotypes in mice. In addition, we use in vitro tissue culture methods in conjunction with genetic and pharmacologic approaches to determine signaling mechanism by which TGFbeta ligands regulate cardiovascular development and function. 

Role of TGFbeta signaling in development of cardiovascular system

TGFbeta family consists of three multifunctional ligand proteins (TGFbeta1, 2, 3). We have generated and characterzated several genetically engineered mouse models with complete null and conditional null alleles for TGFbeta1, TGFbeta2 and TGFbeta3 genes. We have shown that Tgfb2 knockout mice recapitulates multiple cardiovascular manifestations of human congenital heart disease, including double-outlet right ventricle (DORV), persistent truncus arteriosus (PTA), ventricular septal defect (VSD), heart valve malformations, aortic arch artery malformations (interrupted aortic arch, aberrant right subclavian artery and remnant of right dorsal aorta and wall hypoplasia). With these genetically engineered mouse models of TGFbeta ligands we are resolving the questions concerning the differential roles of TGFbeta ligands in heart valve formation and remodeling, epicardial-myocardial interaction during coronary and myocardial development, septation of heart, and aortic arch artery malformation and structural integrity of aortic walls during embryonic development.

Role of TGFbeta ligands in susceptibilty and pathogenesis of aortic aneurysm

Aortic aneurysms or aortic dilation remain asymptomatic until rupture, which is generally a catastrophic and sudden lethal event. Both genetic (e.g., mutations affecting TGFbeta signaling) and environmental agents (e.g., arsenic exposure) are considered risk factors for aortic aneurysm. Both TGFbeta and environmental arsenic exposure are thought to regulate extracellular matrix (ECM) composition of the aortic wall. The mechanical failure of the aortic wall is thought to be involved in aortic rupture or dissection.

We have standardized Microbiaxial Opto-Mechanical approaches to simultaneously and non-invasively investigate the macroscopic (e.g., stress/strain) biaxial biomechanical response and microstructural (extracellular matrix) makeup of small-sized intact tubular aortic samples from mouse and humans. We are using these approaches on Tgfb heterozygous mice to determine the role of TGFbeta ligands in the susceptibility to aortic aneurysm. We are also using these approaches to study the pathogenesis of aortic aneurysm in several genetic mouse models of aneurysm, including Fibrillin-1C1039G/+ (mouse model of Marfan syndrome (MFS) which develop aneurysm but not dissection) Fibrillin-1mgR/mgR (mouse model of MFS which develop aneurysm and dissection). In addition, we are studying the changes in microstructural and biomechanical properties in experimental (Angiotensin II-infused) mouse models of aneurysm. Furthermore, pharmacologic and genetic approaches are used to block or reverse the progress of aneurysm in mouse models of aneurysm. Overall, these studies will provide useful information about the role of TGFbeta ligands in aortic aneurysm, and have implications in developing better diagnostics to identify individuals at risk of developing aortic aneurysm and rupture.

Role of environmental arsenic exposure in the pathogenesis of aortic aneurysm

There is an indication of a link between environmental arsenic exposure and TGFbeta in aortic aneurym. There is also evidence of a connection between the arsenic exposure and ECM remodeling. We are using mouse genetics and Microbiaxial Opto-Mechanical approaches to determine the effect of environmetal arsenic exposure on collagen and elastin microstruture and biomechanical properties in genetic and experimental mouse models of aneurym. We are also investigating the mechanisms by which arsenic exposure is involved in the pathogenesis of aortic aneurysm.

I am also a member of the Sarver Heart Center.