Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm

项目概要 NIH Diversity K01 (RFA-HL-19-026) 申请的申请人是助理 Mary Sheppard 博士 肯塔基大学医学院教授。 Sheppard 博士的研究兴趣领域是 马凡综合征，她在外科设立了主动脉诊所。她的长期职业生涯 目标是开发胸主动脉瘤的新疗法。这个决定是受到她个人的影响 这一诊断面临的挑战。为了寻求更多的治疗选择，谢泼德医生决定开始 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 R01 该项目完成后申请资金。谢泼德博士组建了一支令人印象深刻的指导团队 由博士组成。多尔蒂、卡西斯、格拉夫和米勒维奇。她的主要导师 Daugherty 博士在 他在动脉瘤形成的动物模型方面拥有丰富的专业知识，并且已成功资助 NIH 研究员 几十年。共同导师 Lisa Cassis 博士是肾素-血管紧张素系统和性方面的专家 主动脉瘤的二形性。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。 Dianna Milewicz 博士是医学遗传学专家，从事转化研究 重点关注血管疾病的遗传易感性。所有导师都是具有丰富经验的资深科学家 成功指导新教师获得独立的 NIH 资助。该导师团队将协助 Sheppard 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。拟议的研究将检验 他汀类药物减缓马凡小鼠模型胸主动脉瘤生长的机制 综合症。 Ras法尼基化对动脉瘤生长、Raf/ERK表达、基质的影响 金属蛋白酶活性、弹性蛋白碎片和白细胞积累将在目标 1 中进行评估。 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的影响 动脉瘤将在目标 2 中进行调查。这些研究的结果将构成 R01 的初步数据 研究申请将使谢泼德博士从实习生身份转变为独立的医师科学家。

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.