Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm

项目摘要 本NIH Diversity K 01（RFA-HL-19-026）申请的申请人是助理玛丽谢泼德博士 肯塔基州大学医学院教授。谢泼德博士的研究领域是 马凡氏综合征，她已经建立了一个主动脉诊所在外科。长期职业生涯 目的是为胸主动脉瘤开发新的治疗方法。这一决定受到她个人的影响。 这个诊断的挑战。希望有更多的治疗选择，谢泼德医生决定着手 在基础科学研究方面的额外培训。她的短期目标是研究计划的基础， （1）发展临床前研究技能，使她能够确定新的治疗靶点 血管疾病;（2）确立自己作为动脉瘤研究专家的地位;（3）提交R 01 项目完成后的资金申请。谢泼德博士组建了一个令人印象深刻的指导团队 由Daughter，Cincinnati，Graf和Milewicz博士组成。她的主要导师，Daughter博士， 在动脉瘤形成的动物模型方面的专业知识，他一直是一个成功资助的NIH研究员， 几十年共同导师丽莎博士是一个专家，在肾素血管紧张素系统和性 主动脉瘤的二型性共同导师Greg Graf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Dianna Milewicz博士从事转化研究 专注于血管疾病的遗传易感性。所有导师都是资深科学家， 成功地指导新教师获得独立的NIH资金。这个指导小组将协助谢泼德博士 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细胞分选。拟议的研究将审查 他汀类药物抑制马凡氏小鼠模型胸主动脉瘤生长的机制 综合征Ras法尼基化对动脉瘤生长、Raf/ERK表达、基质 金属蛋白酶活性、弹性蛋白断裂和白细胞积聚将在目标1中评价。的 他汀类药物联合β-肾上腺素受体拮抗剂或血管紧张素受体阻滞剂对胸主动脉影响 将在目标2中研究动脉瘤。这些研究的结果将构成R 01的初步数据 研究申请，这将使谢泼德博士从实习生身份转变为独立的医生科学家。

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.