Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm

项目摘要 这份NIH多样性K01(RFA-HL-19-026)申请的申请人是玛丽·谢泼德博士，她是一名助理 肯塔基大学医学院教授。谢泼德博士的研究兴趣领域是 马凡综合征，她已经在外科建立了一家主动脉诊所。她长期的职业生涯 目的是开发治疗胸主动脉瘤的新疗法。这个决定受到了她个人的影响。 对这一诊断的挑战。由于希望有更多的治疗选择，谢泼德博士决定着手 基础科学研究方面的额外培训。她的短期目标构成了研究计划的基础， 是：(1)发展临床前研究技能，使她能够找到新的治疗靶点进行治疗 血管疾病；(2)确立自己作为动脉瘤研究专家的地位；(3)提交R01 本项目完成后的资金申请。谢泼德博士组建了一支令人印象深刻的指导团队 由多尔蒂博士、卡西斯博士、格拉夫博士和米列维奇博士组成。她的主要导师，多尔蒂博士，有广泛的 在动脉瘤形成的动物模型方面的专业知识，他一直是美国国立卫生研究院成功资助的 几十年了。共同导师丽莎·卡西斯博士是肾素-血管紧张素系统和性行为方面的专家 主动脉瘤的二形性。共同导师格雷格·格拉夫博士是胆固醇代谢和他汀类药物方面的专家。 药理学。医学遗传学专家戴安娜·米列维奇博士从事翻译研究 重点研究血管疾病的遗传易感性。所有导师都是资深科学家，他们的记录是 成功地为新教师提供了独立的国立卫生研究院资助。这支导师团队将协助谢泼德博士 学习实验室技术，包括先进的显微镜、亚细胞分离、 免疫组织化学和荧光激活的细胞分选。拟议的研究将审查 他汀类药物抑制Marfan小鼠模型胸主动脉瘤生长的机制 综合症。RAS法尼化对动脉瘤生长、Raf/ERK表达、基质的影响 在目标1中，将评估金属蛋白酶活性、弹性蛋白断裂和白细胞聚集。 他汀类药物联合β受体拮抗剂或血管紧张素受体阻滞剂对胸主动脉的影响 动脉瘤将在AIM 2中进行调查。这些研究的结果将形成R01的初步数据 研究申请，将谢泼德博士从实习生身份转变为独立的内科科学家。

Project Summary The applicant for this NIH Diversity K01 (RFA-HL-19-026) application is Dr. Mary Sheppard, an Assistant Professor at the University of Kentucky, College of Medicine. Dr. Sheppard’s area of research interest is Marfan syndrome, and she has established an Aortic Clinic in the Department of Surgery. Her long term career goal is to develop new therapeutics for thoracic aortic aneurysm. This decision was influenced by her personal challenges with this diagnosis. Desiring more treatment options, Dr. Sheppard has decided to embark on additional training in basic science research. Her short term goals, which form the basis for the research plan, are: (1) to develop preclinical research skills that will enable her to identify new therapeutic targets to treat vascular diseases; (2) to establish herself as an expert in aneurysm research; and (3) to submit an R01 funding application upon this project’s completion. Dr. Sheppard has assembled an impressive mentoring team composed of Drs. Daugherty, Cassis, Graf, and Milewicz. Her primary mentor, Dr. Daugherty, has extensive expertise in animal models of aneurysm formation, and he has been a successfully funded NIH investigator for several decades. Co-mentor Dr. Lisa Cassis is an expert in the renin-angiotensin system and sexual dimorphism of aortic aneurysms. Co-mentor Dr. Greg Graf is an expert in cholesterol metabolism and statin pharmacology. Dr. Dianna Milewicz, an expert in medical genetics, has a career in translational studies focused on genetic predisposition to vascular diseases. All mentors are senior scientists with a track record of successfully mentoring new faculty to independent NIH funding. This mentor team will assist Dr. Sheppard in learning laboratory techniques which include advanced microscopy, subcellular fractionation, immunohistochemistry, and fluorescence activated cell sorting. The proposed research will examine the mechanisms by which statins attenuate thoracic aortic aneurysm growth in a mouse model of Marfan syndrome. The impact of Ras farnesylation on aneurysm growth, Raf/ERK expression, matrix metalloproteinase activity, elastin fragmentation, and leukocyte accumulation will be evaluated in Aim 1. The impact of statin combined with β-adrenoceptor antagonist or angiotensin receptor blocker in thoracic aortic aneurysm will be investigated in Aim 2. The findings of these studies will form the preliminary data for an R01 research application which will transition Dr. Sheppard from trainee status to independent physician-scientist.