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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.

项目总结