R01HL162928

The role of arylsulfatase in vascular calcification - project summary

Vascular calcification is a hallmark of atherosclerotic cardiovascular diseases such as myocardial infarction and stroke, which are the leading causes of morbidity and mortality in the world. Although coronary artery calcification (CAC) is a strong independent risk factor for cardiovascular disease, the genetic determinants of CAC and the molecular mechanisms of vascular calcification remain incompletely elucidated.

In a multi-cohort study with more than 22,000 participants, we identified single nucleotide polymorphisms in the arylsulfatase E (ARSE) locus that are associated with coronary artery calcification. In an in vitro model of calcification, our preliminary experiments demonstrated that inhibition of ARSE or a related protein sulfatase 1 (SULF1) prevented the calcification of coronary and aortic vascular smooth muscle cells (VSMCs). Furthermore, we found that SULF1-deficient mice are protected from developing vascular calcification.

Based on our preliminary evidence, combining a human genome-wide association study, in vitro VSMC experiments, and an in vivo murine model of vascular calcification, we have identified ARSE and SULF1 to be novel activators of vascular calcification. The overall objective of this proposal is to understand the molecular mechanisms by which these sulfatases promote vascular calcification and atherosclerosis.

First, using a series of VSMC functional assays, we propose to determine the specific role of ARSE and SULF1 in promoting VSMC osteogenic phenotype switch and calcification. We will also ascertain whether the sulfatases induce the development of vascular calcification and atherosclerosis in vivo using mouse models.

Second, we have uncovered an important role for ARSE and SULF1 in regulating autophagy and bone morphogenetic protein (BMP) signaling. We will determine if the effects of ARSE and SULF1 on VSMC-mediated vascular calcification are dependent on their effects on autophagy and/or BMP signaling.

Lastly, we will examine the associations of the ARSE index variant with a range of electronic health record phenotypes, as well as with additional vascular calcification phenotypes including aortic calcium volume and density, aortic valve calcification, and mitral annular calcification. Furthermore, we will conduct the first genome-wide association study to identify novel genetic determinants of coronary calcification density.

The experiments proposed will provide important mechanistic insights into the function of sulfatases in the vasculature and into the underlying molecular and genetic mechanisms of vascular calcification and atherosclerosis.

The General Hospital Corporation

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. 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]

Boston, Massachusetts 021142621 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 84% from $1,418,406 to $2,611,827.