The Role of zbtb46 in Endothelial Cell Activation

zbtb46 在内皮细胞激活中的作用

基本信息

批准号：
9232183
负责人：
Amir Rezvan
金额：
$ 16.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-05 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232183
关键词：
3&apos Untranslated Regions Affect American Animal Model Antigens ApoE knockout mouse Apolipoprotein E Area Arteries Atherosclerosis Award Basic Science Binding Biology Blood Vessels Cardiology Cardiovascular Diseases Cell Proliferation Cells Cellular biology Cessation of life Chest Pain Computer Simulation Cone Coronary heart disease Data Dendritic Cells Devices Down-Regulation Educational process of instructing Endothelial Cells Endothelium Epigenetic Process Fellowship Program Funding Future Gene Expression Gene Targeting Genes Goals Heart failure High Fat Diet I-kappa B Proteins ICAM1 gene Immune Immunology In Vitro Inflammatory Innate Immune System Internal Medicine Iran Knock-out Knockout Mice Lead Leukocytes Ligation Mediating Medical Mentors Messenger RNA MicroRNAs Migration Assay Modeling Morbidity - disease rate Mus Myocardial Infarction NR4A1 gene Nuclear PDGF Signaling Pathway Pathway Analysis Pathway interactions Philadelphia Physicians Play Principal Investigator Process Proteins Publishing RNA Regulation Relaxation Research Research Personnel Residencies Role Science Scientist Signal Transduction Small Interfering RNA Stimulus Stroke System Techniques Testing Time Training Transcription Repressor/Corepressor United States Universities Up-Regulation atheroprotective base clinical practice endothelial dysfunction feeding immune activation inhibitor/antagonist insight interest knock-down mortality mouse model new therapeutic target novel novel therapeutics overexpression prevent professor public health relevance response shear stress statistics therapeutic candidate therapeutic target transcriptome vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): The goal of this K08 mentored award is to provide funding for developing the principal investigator (PI) into an independent physician-scientist in the field of cardiovascular disease. The PI, Dr. Amir Rezvan, obtained his MD degree from Iran University of Medical Sciences, followed by an MS degree in Biomedical Science from Drexel University in Philadelphia, where he studied the effects of shear stress on the endothelium. He then completed his Internal Medicine residency at Drexel University and moved to Atlanta to continue his training in Cardiovascular Disease in a four year basic science research track fellowship program at Emory University. He then joined the Division of Cardiology at Emory University as an Assistant Professor. He is currently a licensed physician in the State of Georgia and is certified by the American Board of Internal Medicine in both Internal Medicine and Cardiovascular Disease. He will be allocating 75% of his time to research proposed in this application and 25% of his time to practicing clinical cardiology and teaching residents and fellows in the university setting. This project will focus on the role of shear stress regulated ZBTB46 expression in endothelial cells (ECs) on EC activation. The PI will test the hypothesis that ZBTB46, a transcription repressor responsible for preventing immune activation in dendritic cells, is expressed under laminar shear conditions in ECs and is downregulated by disturbed flow, leading to activation of ECs. The PI will then test the role of shear sensitive miRs with potential targeting of ZBTB46 on its down-regulation by disturbed flow. He will then test the hypothesis that alterations in ZBTB46 levels in ECs (by down-regulating or overexpressing) will alter EC gene expression, specifically potential target genes for ZBTB46 such as NR4A1(NFkB inhibitor), PDGFC, and NFkB mediated genes such as VCAM1 and ICAM1 as well as affecting EC proliferation and tubule formation. Lastly, the PI will test the hypothesis that knockdown of ZBTB46 in an animal model leads to increased endothelial dysfunction and atherosclerosis. Dr. Rezvan will benefit from a team of mentors including Dr. Hanjoong Jo, an established investigator and expert in vascular biology, Dr. W. Robert Taylor, a physician-scientist and expert in vascular inflammation, Dr. Arash Grakoui, an established investigator in the field of immunology, and Dr. Jeremy Boss, an established investigator and expert in gene expression and epigenetics. This group of mentors will provide additional expertise and training needed for the PI to reach his short term goal of achieving scientific independence while furthering the understanding of role of ZBTB46 in EC activation, leading to his long term goal of becoming an established physician-scientist and succeeding in developing novel therapies to prevent and treat atherosclerotic disease while mentoring younger physicians and scientists.

描述（由申请人提供）：该 K08 指导奖的目标是为将首席研究员 (PI) 培养成为心血管疾病领域的独立医师科学家提供资金。该 PI 博士 Amir Rezvan 获得了医学博士学位。他在伊朗医科大学获得了学士学位，随后在费城德雷塞尔大学获得了生物医学科学硕士学位，在那里他研究了剪切应力对内皮的影响，然后在德雷塞尔大学完成了内科住院医师实习。并搬到亚特兰大，在埃默里大学继续接受为期四年的基础科学研究跟踪奖学金计划的心血管疾病培训，然后加入埃默里大学心脏病学系担任助理教授。他目前是该州的执业医师。他将分配 75% 的时间用于本申请中提出的研究，并将 25% 的时间用于临床心脏病学以及向住院医师和研究员进行教学。大学该项目将重点研究内皮细胞 (EC) 中剪切应力调节的 ZBTB46 表达对 EC 激活的作用，PI 将测试 ZBTB46（一种负责阻止树突状细胞中免疫激活的转录抑制因子）在层流下表达的假设。 EC 中的剪切条件会被扰动的流动下调，从而导致 EC 的激活。然后 PI 将测试剪切敏感 miR 的作用，并具有潜在的靶向作用。然后，他将测试 EC 中 ZBTB46 水平的改变（通过下调或过度表达）将改变 EC 基因表达，特别是 ZBTB46 的潜在靶基因（例如 NR4A1（NFkB 抑制剂））的假设。、PDGFC 和 NFkB 介导的基因（例如 VCAM1 和 ICAM1）以及影响 EC 增殖和肾小管形成最后，PI 将检验该假设。在动物模型中，ZBTB46 的降低会导致内皮敲击功能障碍和动脉粥样硬化增加，Rezvan 博士将受益于包括 Hanjoong Jo 博士（血管生物学领域知名研究者和专家）、W. Robert Taylor 博士在内的导师团队。该小组由血管炎症领域的医师科学家和专家、免疫学领域的知名研究者 Arash Grakoui 博士和基因表达和表观遗传学领域的知名研究者和专家 Jeremy Boss 博士组成。导师将为 PI 提供所需的额外专业知识和培训，以实现其实现科学独立的短期目标，同时进一步了解 ZBTB46 在 EC 激活中的作用，从而实现他成为一名成熟的医师科学家并在开发预防和治疗动脉粥样硬化疾病的新疗法，同时指导年轻的医生和科学家。