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

• 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
• 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

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.

项目总结/摘要 本提案描述了一个为期5年的培训计划，以发展心血管领域的学术生涯 research. Lino Cardenas博士将在100多名研究人员的环境中获得多名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 完成了他在申请中列出的研究计划。利诺·卡德纳斯博士的研究项目 血管钙化的分子机制，与急性冠脉病变的发病机制高度相关， 综合征、动脉粥样硬化和外周动脉疾病。越来越多的证据指向自噬， 进化上保守的过程，在早期动脉粥样硬化过程中起保护作用。然而，自噬可以 在晚期动脉粥样硬化中变得失调。在初步研究中，利诺·卡德纳斯博士观察到 自噬途径的药理学激活减少了Mgp-/-小鼠（小鼠 自发性血管钙化模型）并提高存活率。候选人建议将 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，候选人的第一个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的发展， 调节自噬可以抑制血管钙化。利诺·卡德纳斯博士会将他的初步发现 通过结合RNA-seq，ChIP-seq和ATAC-seq技术来确定染色质可塑性对细胞增殖的影响， 自噬途径在血管钙化过程中的作用。利诺·卡德纳斯博士将研究一系列 自噬调节剂对VSMC表型和钙化的影响。在目标2中，候选人将 确定自噬通路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的小鼠模型。提高对新分子的认识 负责血管钙化的机制可能具有重要的临床意义， 治疗心血管疾病的靶点。候选人的目标是立即完成以下任务 和长期职业目标：（1）更广泛地了解导致 血管钙化(2)学习使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多态性。此外，Lino博士 卡德纳斯将学习先进的分子生物学技术和条件基因删除在多个鼠 模型(3)在导师和咨询委员会的指导下，发展 指导实验室，促进富有成效的研究合作和赠款写作（4）要成功申请 R01基金在他的奖项启动的3年内。