Determinants of Aorta Heterogeneity

Grants and Contracts Details

Description

Thoracic aortic aneurysm and dissection (TAAD) has high risk for fatal aortic rupture. The pathogenesis of TAAD is complex, spanning a spectrum of known genetic and unknown spontaneous etiologies. Mechanisms of TAAD have not been defined, which impede the development of effective medical treatment. Conflicting interpretations of animal and human study findings also result in challenges to fully understand the development and progression of this disease. Many mouse models are available, each representing some, but not all aspects of the TAAD pathogenesis and mechanisms of the human disease. This proposed R35 Research Program will primarily focus on understanding the complex pathophysiology and mechanisms of TAAD using multiple mouse models with manipulations of a spectrum of molecules. The potential causal findings in mouse models will be validated in human TAAD samples from Dr. LeMaire at the Baylor College of Medicine. Dr. LeMaire has established a Thoracic Aortic Disease Tissue Bank housing samples and corresponding phenotypic data from over 4,000 patients with TAAD and has served as a core for the NHLBI-supported Specialized Center of Clinical Oriented Research (SCCOR) in TAAD. Three major projects are proposed in this program. Project 1 aims to define the renin-angiotensin system-mediated mechanisms and therapeutic potential for TAAD; Project 2 will determine whether smooth muscle cell heterogeneity is a basis for regional and transmural location of pathology in TAAD; Project 3 will explore how the extracellular matrix and crosstalk between smooth muscle cells and fibroblasts contribute to TAAD development. We have robust tools including a spectrum of reagents, multiple classic and new mouse models, ultrasonography, MRI, and state-of-the-art intravital microscopy, proteomics, and single cell RNA sequencing techniques. In addition to aortic aneurysms, the PI has more than 30-year expertise in the fields of lipoprotein metabolism, inflammation, and atherosclerosis research. TAAD is not a sole aortic disease, but is associated with a wide range of diseases or syndromes that may affect skin, lung, kidney, brain, bone, and other organs. The proposed research program will benefit from the flexibility to pursue potential contributions of other tissues and organs to TAAD, and vice versa the influences of TAAD on other tissues and organs.
StatusActive
Effective start/end date6/1/215/31/28

Funding

  • National Heart Lung and Blood Institute: $839,592.00

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