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

血管平滑肌细胞介导大小动脉钙化的新分子机制

基本信息

批准号：
10670415
负责人：
Christian Lacks Lino Cardenas
金额：
$ 16.16万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670415
关键词：
ATAC-seq Acceleration Adult Advisory Committees Affect Aorta Arteries Atherosclerosis Autophagocytosis Autophagosome Award Blood Vessels Calciphylaxis Cardiovascular Diseases Cardiovascular system Cell model Cells Cessation of life ChIP-seq Chromatin Chromatin Structure Chronic Kidney Failure Clinical Collaborations Complex Core Facility Dangerousness Data Defect Deposition Dermal Development Diabetes Mellitus Disease Disease Progression Disease model Dose Environment Epigenetic Process Event Faculty Fostering Funding Gene Deletion Genes Genetic Genetic Databases Genetic Polymorphism Goals Grant Homeostasis Human Human Genetics In Vitro Investigation Knowledge Laboratories Learning Medial Mediating Membrane Mentors Messenger RNA Modeling Molecular Molecular Biology Morbidity - disease rate Mus Pathogenesis Pathway interactions Patients Peripheral arterial disease Phenotype Predictive Factor Process Productivity Program Development Protein Deficiency Relaxation Reporting Research Research Personnel Role Sirolimus Smooth Muscle Myocytes Specimen Techniques Technology Testing Therapeutic Therapeutic Effect Therapeutic Studies Training Programs Transmission Electron Microscopy United States Vacuole Vascular Smooth Muscle Vascular calcification Vesicle Writing acute coronary syndrome advanced disease calcification calcium phosphate cardiovascular risk factor career effective therapy experimental study extracellular improved in vivo inhibition of autophagy inhibitor insight matrix Gla protein member mortality mouse model novel osteogenic pharmacologic prevent programs promoter skills small molecule inhibitor success transcriptome sequencing treatment strategy

项目摘要

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.

项目概要/摘要该提案描述了一个为期 5 年的心血管学术职业发展培训计划研究。 Lino Cardenas 博士将从超过 100 名研究人员的环境中获得多位研究人员的专业知识教师，并将可以使用 MGH/HMS 的各种生物医学核心设施，以帮助成功完成其申请中概述的研究计划。 Lino Cardenas 博士的研究项目重点血管钙化分子机制研究，与急性冠脉发病机制高度相关综合征、动脉粥样硬化和外周动脉疾病。越来越多的证据表明自噬是一种进化上保守的过程，在早期动脉粥样硬化期间具有保护作用。然而，自噬可以因晚期动脉粥样硬化而失调。在初步研究中，Lino Cardenas 博士观察到自噬途径的药理激活可减少 Mgp-/- 小鼠（小鼠自发性血管钙化模型）并提高生存率。候选人提议定义自噬破坏加剧血管钙化的精确分子机制以下两个目标：在目标 1 中，考生的首要目标是确定血管平滑肌的作用细胞（VSMC）特异性自噬失调对血管钙化发展的影响以及是否自噬的调节可能抑制血管钙化。利诺·卡德纳斯博士将扩展他的初步发现通过结合 RNA-seq、ChIP-seq 和 ATAC-seq 技术来定义染色质可塑性对血管钙化过程中的自噬途径。 Lino Cardenas 博士将研究一系列的治疗效果自噬调节剂对 VSMC 表型和钙化的体外和离体影响。在目标 2 中，候选人将确定自噬途径的药理学或遗传激活是否抑制血管钙化在体内使用两种不同的血管钙化小鼠模型。增强新分子的知识血管钙化的机制可能具有重要的临床意义并提供新的治疗心血管疾病的目标。候选人的目标是立即完成以下任务和长期职业目标：（1）对分子机制有更广泛的了解血管钙化。 (2) 学习利用现有人类遗传数据库进行基因组表型分析鉴定与血管表型相关的自噬起始基因的多态性。此外，利诺博士卡德纳斯将学习分子生物学和多只小鼠条件基因删除的先进技术模型。 (3) 在导师和顾问委员会的指导下发展必要的技能指导实验室、促进富有成效的研究合作和资助撰写 (4) 成功申请在其奖项启动后 3 年内获得 R01 资助。