R35HL155649

Determinants of Aorta Heterogeneity - Abstract

Aortopathies, including aneurysms, dissection, and rupture, represent a key challenge in HLBS research. In the past twenty years of our continuously funded research on aortopathies, we have contributed to many mechanistic insights into the aortopathy research, including a new concept: there are regional characteristics of the aorta in regard to diverse embryonic origins and functions of cells.

The overall hypothesis of this R35 program is that heterogeneity of cellular origins imparts functional variances along the length of the aorta, including diversity of extracellular matrix stability, which in turn contributes to regional specificity of aortopathies. Regional specificity of aortopathies is present in many mouse models that we have validated and characterized. Our initial single-cell transcriptomic and proteomic data have also implicated new potential contributors to heterogeneity of the normal aortic biology and aortopathies.

Three major themes are proposed in this program:

(1) What are the structural and molecular mechanisms that contribute to biological and pathophysiological heterogeneity along the length of the aorta?

(2) Are cellular and extracellular heterogeneity a basis for regional specificity of aortopathies?

(3) How do signaling pathways, extracellular matrix, and crosstalk between resident aortic cells coordinate to promote the heterogeneity of aortopathies?

We have robust tools, including a spectrum of reagents, multiple classic and new mouse models, ultrasonography, MRI, intravital microscopy, proteomics, and single-cell RNA sequencing techniques. In addition to aortopathy research, the PI has more than 30-year expertise in the fields of lipoprotein metabolism, inflammation, and atherosclerosis research.

Aortopathies are not a sole aortic disease but are associated with a wide range of diseases or syndromes that may affect the 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 aortopathies, and vice versa, the influences of aortopathies on other tissues and organs.

This R35 mechanism will also benefit the PI's strength in basic research, enhance his interaction with translational research in the clinical arena, and train the next generation of scientists.

University Of Kentucky Research Foundation

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Lexington, Kentucky 405060004 United States

Single Zip Code

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-20-011)

Amendment Since initial award the total obligations have increased 656% from $596,149 to $4,507,868.