Research Assistant Professor

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Address: BIO5 Institute
University of Arizona
MRB322, 1656 E Mabel St
PO Box 245217


Tucson, AZ 85724-5217
Phone: 520-626-6644
E-Mail: azharm@email.arizona.edu

Research Interests

My current research is focussing on the role of Transforming Growth Factor beta (TGFbeta) signaling in cardiovascular development and pathogenesis of heart valve diseases and aortic aneurysm. The goal of my translational biomedical research is to determine the role of genetic and environmental (e.g., arsenic exposure) factors in the susceptibility and pathogenesis of cardiovascular diseases and develop novel approaches for an early detection and prevention and medical treatment of these diseases.

My research is currently supported by grants from Arizona Biomedical Research Commission (ABRC) (PI: Azhar), The Steven M. Gootter Foundation (PI: Azhar), and The Stephen Michael Schneider Investigator Award for Pediatric Cardiovascular Research and The William J. “Billy” Gieszl Endowment for Heart Research (PI: Azhar); and The National Institutes of Heart, Lung and Blood (NHLBI) (Co-PI: Azhar).

I use mouse genetic engineering, molecular, cellular and developmental biology techniques, and state-of-the-art opto-mechanical approaches (intravital multi-photon imaging coupled with micro-biaxial biomechnical device) 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 and pathogenesis of cardiovascular diseases. 

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, second heart-field-derived cardiac progenitor cells, 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. Current clinical diagnostic tests are not sufficient to predict the risk of lethal aortic dissection or rupture in aneurysmal patients.

We have developed 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. I am using these approaches on Tgfb heterozygous mice and mice with induced physiological stress (ANG2-treated) to determine the role of TGFbeta ligands and physiological stress (i.e., blood pressure and inflammation) 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-1^C1039G/+ (mouse model of Marfan syndrome (MFS) which develop aneurysm but not dissection) Fibrillin-1^mgR/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 natural progression of latent aortic disease to aortic aneurysm or rupture and 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 low environmetally relevant doses of arsenic on the collagen and elastin microstruture and biomechanical properties in genetic and experimental mouse models of aneursym. We are also investigating the dysregulated TGFbeta signaling is the mechanism by which arsenic exposure is involved in the pathogenesis of aortic aneurysm.

Collectively, our translational biomedical research is providing us novel information about the role of TGFbeta ligands in development and pathogenesis of cardiovascular diseases, and has enormous potential in developing better and novel diagnostic and therapeutic strategies for the patients of cardiovascular diseases.

Member:

Advanced Research Institute of Biomedical Imaging, U of A

Sarver Heart Center, U of A

Selected Publications

Liao S, Bodmer JR, Azhar M, Newman G, Coffin JD, Doetschman T, Schultz JE. Jan 2010. The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury.. J Mol Cell Cardiol, Jan 29:[ahead of print]

Liao S*, Bodmer J*, Pietras D*, Azhar M*, Doetschman T, Schultz Jel J. Feb 2009. Biological functions of the low and high molecular weight protein isoforms of fibroblast growth factor-2 in cardiovascular development and disease.. Dev Dyn., 238(2):249-64 *Co-First Aut

Azhar M, Yin M, Zhou M, Li H, Mustafa M, Nusayr E, Keenan JB, Chen H, Pawlosky S, Gard C, Grisham C, Sanford LP, Doetschman T.. Feb 2009. Gene targeted ablation of high molecular weight fibroblast growth factor-2.. Dev Dyn., 238(2):351-7

Azhar M, Runyan RB, Gard C, Sanford LP, Miller ML, Andringa A, Pawlowski S, Rajan S, Doetschman T.. Feb 2009. Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development.. Dev Dyn., 238(2):431-42