Novel molecular mechanisms of vascular smooth muscle cell-mediated large and small artery calcification

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year training program for the development of an academic career in cardiovascular research. Dr. Lino Cardenas will gain from the expertise of multiple investigators in an environment of over 100 faculty and will have access to a wide range of biomedical core facilities at MGH/HMS to aid in the successful completion of the research program outlined in his application. Dr. Lino Cardenas's research program focuses on the molecular mechanisms of vascular calcification, highly relevant to the pathogenesis of acute coronary syndromes, atherosclerosis, and peripheral arterial disease. Growing evidence points towards autophagy, an evolutionarily conserved process, as being protective during early atherosclerosis. However, autophagy can become dysregulated with advanced atherosclerosis. In preliminary studies, Dr. Lino Cardenas has observed that pharmacologic activation of the autophagy pathway reduces vascular calcification in Mgp-/- mice (mouse model of spontaneous vascular calcification) and improves survival. The candidate proposes to define the precise molecular mechanisms by which disruption of autophagy exacerbates vascular calcification with the following two aims: In Aim 1, the candidate's first objective is to determine the role of vascular smooth muscle cell (VSMC)-specific autophagy dysregulation on the development of vascular calcification and whether modulation of autophagy may inhibit vascular calcification. Dr. Lino Cardenas will extend his preliminary findings by combining RNA-seq, ChIP-seq and ATAC-seq technologies to define the effects of chromatin plasticity on the autophagy pathway during vascular calcification. Dr. Lino Cardenas will study the therapeutic effect of a range of autophagy modulators on VSMC phenotype and calcification in vitro and ex vivo. In Aim 2, the candidate will determine whether pharmacologic or genetic activation of the autophagy pathway inhibits vascular calcification in vivo using two different murine models of vascular calcification. Enhancing knowledge of novel molecular mechanisms responsible for vascular calcification may hold important clinical implications and provide new targets for the treatment of cardiovascular disease. The candidate aims to accomplish the following immediate and long-term career goals: (1) To develop a broader understanding of the molecular mechanisms resulting in vascular calcification. (2) To learn genomice-phenotype analyses using existing human genetic databases to identify polymorphisms in autophagy initiation genes associated with vascular phenotypes. Additionally, Dr. Lino Cardenas will learn advanced techniques in molecular biology and conditional gene deletion in multiple murine models. (3) To develop under the guidance of his mentors and advisory committee the necessary skills of directing a laboratory, fostering productive research collaborations and grant writing (4) To successfully apply for R01 funding within 3 years of his award initiation.