Mechanisms for miR-30e Regulated Atherogenic Pathways with Age

简介(申请人提供)：Shehadeh博士拥有微生物学学士学位，计算生物学博士和博士后培训，以及心血管研究博士后培训。她是密歇根大学医学系心脏科终身教职的初级教员。这一职业发展奖补充了她在核心分子生物学、血管老化和动脉粥样硬化方面的高级导师和基于实验室的教学培训的研究背景。这项研究计划基于初步观察，这些观察支持这样的假设，即microRNA miR-30e随着年龄的增长而下调，并调节主要的动脉粥样硬化形成途径。这一假说将按照三个目标进行检验：(1)评估miR-30E通过调节HMGcr对青年、中年和老年动脉粥样硬化小鼠胆固醇生物合成和生物活性的影响(2)确定miR-30e介导的平滑肌标志物调控的分子机制，以及(3)确定miR-30e抑制间充质干细胞(MSCs)成骨分化的机制。谢哈德博士将实施一项职业发展计划，包括：1.实验研究、实验室指导、期刊俱乐部，以及导师和同事的科学审查和发展。2.迈阿密大学研究生课程。3.内部研讨会和国家会议和专题讨论会。4.负责任地进行研究方面的培训。5.由五名高级博士和一名高级博士组成的科学咨询委员会的指导。6.赠款的编写、赠款审查和制定旨在实现独立的过渡计划。谢哈德博士的分子和血管生物学导师将主要来自血管生物研究所(VBI)主任基思·韦伯斯特博士。韦伯斯特博士是美国国立卫生研究院资助的一位成就卓著的血管生物学家，他研究缺氧调节血管生成的机制、动脉粥样硬化、间充质干细胞的老化以及内皮祖细胞的治疗潜力。谢哈德博士将由跨学科干细胞研究所(ISCI)主任约书亚·黑尔博士共同指导。黑尔博士由美国国立卫生研究院资助进行调查 关于间充质干细胞和心脏干细胞的基础和临床研究，在再生医学方面有着长期的研究记录，并将就据信是骨髓间充质干细胞分化基础的关键机制途径提供指导。这个指导团队将指导Shehadeh博士的职业发展，因为她在3年内执行了这项申请的研究目标，在第二年写下了她的R01，并过渡到作为一名研究科学家的独立。

DESCRIPTION (provided by applicant): Dr. Shehadeh has a B.S. in Microbiology, a Ph.D and postdoctoral training in computational biology, and postdoctoral training in cardiovascular research. She is a junior faculty on the tenure track in the Division of Cardiology at the Department of Medicine at UM. This career development award supplements her research background with senior mentorship and lab-based and didactic training in core molecular biology, vascular aging and atherosclerosis. The research plan is based on preliminary observations which support the hypothesis that a microRNA, miR-30e, is down regulated with age and regulates major atherogenic pathways. This hypothesis will be tested along three aims: (1) to assess the effect of miR-30e on cholesterol biosynthesis and bioactivity via Hmgcr regulation, in young, middle-aged, and old atherogenic mice (2) identify the molecular mechanism of miR-30e-mediated regulation of smooth muscle markers, and (3) identify mechanism by which miR-30e suppresses osteogenic differentiation of mesenchymal stem cells (MSCs). Dr. Shehadeh will undertake a career development plan consisting of: 1. Experimental research, laboratory instruction, journal clubs and scientific review and development by her mentors and colleagues. 2. Coursework through the University of Miami graduate program. 3. Intramural seminars and national conferences and symposia. 4. Training in the responsible conduct of research. 5. Guidance by a scientific advisory committee consisting of five senior MDs and one senior Ph.D. 6. Grant writing, grant review, and development of a transition plan aimed at independence. Dr. Shehadeh's molecular and vascular biology mentorship will primarily come from Dr. Keith Webster, director of Vascular Biology Institute (VBI). Dr. Webster is an accomplished NIH-funded vascular biologist who studies mechanisms of hypoxia-regulated angiogenesis, atherosclerosis, aging of mesenchymal stem cells, and therapeutic potential of endothelial progenitor cells. Dr. Shehadeh will be co-mentored by Dr. Joshua Hare, director of the Interdisciplinary Stem Cell Institute (ISCI). Dr. Hare is NIH-funded to investigate basic and clinical research on mesenchymal and cardiac stem cells, has a long track record of research in regenerative medicine, and will provide guidance regarding key mechanistic pathways believed to underlie differentiation of mesenchymal stem cells. This mentorship team will guide Dr. Shehadeh's career development as she executes the research aims of this application in the 3 years, writes her R01 on the 2nd year, and transitions to independence as a research scientist.