Pharmacological Mechanistic Insights into Thoracic Aortic Aneurysm

胸主动脉瘤的药理学机制见解

基本信息

批准号：
10320451
负责人：
Mary Burchett Sheppard
金额：
$ 16.2万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-18 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10320451
关键词：
Adrenergic Receptor Aneurysm Angiotensin Receptor Animal Model Aorta Aortic Aneurysm Aortic Diseases Aortic Rupture Area Atenolol Attenuated Basic Science Biological Assay Blood Vessels Cause of Death Cell Fractionation Cell membrane Cellular Membrane Chest Cholesterol Cholesterol Homeostasis Clinic Clinical Research Confocal Microscopy Cultured Cells Data Diagnosis Disease Dissection Elastin Etiology FBN1 Faculty Farnesyl Transferase Inhibitor Fluorescence-Activated Cell Sorting Funding Future Gel Gelatinase A Genetic Diseases Genetic Predisposition to Disease Goals Growth Human Hydroxymethylglutaryl-CoA reductase Hypertension Immunohistochemistry Incubated Infusion procedures Kentucky Laboratories Laboratory Study Lead Learning Leukocytes Life Losartan Marfan Syndrome Matrix Metalloproteinases Measurement Measures Medical Genetics Medicine Mentors Microscopy Mus Operative Surgical Procedures Patients Persons Pharmaceutical Preparations Pharmacology Physicians Plasma Pravastatin Production Proteins Publications RAS inhibition Ras/Raf Regimen Renin-Angiotensin System Research Research Personnel Research Project Grants Retrospective Studies Risk Scientist Senior Scientist Signal Transduction Signaling Molecule Smooth Muscle Myocytes Syndrome Techniques Testing Therapeutic Uses Thoracic Aortic Aneurysm Tissues Training Transforming Growth Factor beta United States National Institutes of Health Universities Vascular Diseases Vascular Smooth Muscle Work antagonist base career clinically relevant college experimental study farnesyl pyrophosphate farnesylation in vivo insight interest mouse model new therapeutic target novel therapeutics pre-clinical research prevent professor repaired sexual dimorphism skills standard of care translational study ultra high resolution ultrasound

项目摘要

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.

项目摘要该NIH多样性K01（RFA-HL-19-026）申请的申请是助理玛丽·谢泼德（Mary Sheppard）博士肯塔基大学医学院的教授。 Sheppard博士的研究领域是马凡氏综合症，她在手术系建立了一个主动脉诊所。她的长期职业目标是为胸动脉瘤开发新的治疗剂。这个决定受她的个人影响这种诊断面临的挑战。 Sheppard博士希望获得更多的治疗选择基础科学研究的其他培训。她的短期目标是研究计划的基础是：（1）发展临床前研究技能，使她能够确定新的治疗靶标的血管疾病；（2）确立自己的动脉瘤研究专家；（3）提交R01 该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心理团队由Drs组成。 Daugherty，Cassis，Graf和Milewicz。她的主要导师Daugherty博士很广泛动脉瘤形成动物模型的专业知识，他是一名成功资助的NIH研究者几十年。 Co-Mentor Lisa Cassis博士是肾素 - 血管紧张素系统和性的专家主动脉瘤的双态性。 Greg Graf博士是胆固醇代谢和他汀类药物的专家药理。医学遗传学专家Dianna Milewicz博士从事转化研究职业专注于血管疾病的遗传易感性。所有导师都是高级科学家成功地为独立的NIH资助而成功的新教师。这个心理团队将协助Sheppard博士学习实验室技术，包括高级显微镜，亚细胞分馏，免疫组织化学和荧光激活的细胞分选。拟议的研究将研究他汀类药物减弱胸动脉瘤的机制综合征。 Ras Farnesylation对动脉瘤生长，RAF/ERK表达，基质的影响金属蛋白酶活性，弹性蛋白片段化和白细胞积累将在AIM 1中评估。他汀类药物与β-肾上腺素受体拮抗剂或血管紧张素受体阻滞剂在胸腔主动脉中的影响动脉瘤将在AIM 2中进行研究。这些研究的发现将构成R01的初步数据研究应用程序将将谢泼德博士从学员身份转变为独立的身体科学家。