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：
10532213
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/10532213
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A 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 Cholesterol Cholesterol Homeostasis Clinic Clinical Research Confocal Microscopy Cultured Cells Data Diagnosis Disease Dissection Elasticity 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 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 Oxidoreductase Patients Persons Pharmaceutical Preparations Pharmacology Physicians Plasma Pravastatin Production Proteins Publications RAS inhibition Regimen Renin-Angiotensin System Research Research Personnel Research Project Grants Retrospective Studies Risk Scientist Senior Scientist Signal Transduction Signaling Molecule Smooth Muscle Myocytes Techniques Testing Therapeutic Uses Thoracic Aortic Aneurysm Thoracic aorta Tissues Training Transforming Growth Factor beta United States National Institutes of Health Universities Vascular Diseases Vascular Smooth Muscle Work antagonist ascending aorta career clinically relevant college experimental study farnesyl pyrophosphate farnesylation in vivo insight interest mouse model new therapeutic target novel therapeutics pharmacologic 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谢泼德博士的研究兴趣领域是马凡综合征，她在外科部门建立了主动脉诊所，这是她的长期职业生涯。目标是开发胸主动脉瘤的新疗法。这个决定受到了她个人的影响。由于需要更多的治疗选择，谢泼德医生决定着手进行这一诊断。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点血管疾病；(2) 确立自己作为动脉瘤研究专家的地位；以及 (3) 提交 R01 该项目完成后，谢泼德博士组建了一支令人印象深刻的指导团队。由 Daugherty、Cassis、Graf 和 Milewicz 博士组成，她的主要导师 Daugherty 博士拥有广泛的知识。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。主动脉瘤的二态性共同导师 Greg Graf 博士是胆固醇代谢和他汀类药物方面的专家。 Dianna Milewicz 博士是医学遗传学专家，从事转化研究。专注于血管疾病的遗传倾向，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 博士完成这项工作。学习实验室技术，包括先进的显微镜、亚细胞分离、拟议的研究将检查免疫组织化学和荧光激活细胞分选。他汀类药物减缓马凡小鼠模型胸主动脉瘤生长的机制 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。