The Role of zbtb46 in Endothelial Cell Activation

 描述(由申请人提供)：这个K08导师奖的目标是为将首席研究员(PI)发展成为心血管疾病领域的独立内科科学家提供资金。这位PI是Amir Rezvan博士，他在伊朗医科大学获得医学博士学位，然后在费城德雷克塞尔大学获得生物医学硕士学位，在那里他研究了切应力对内皮的影响。然后，他完成了在德雷克塞尔大学的内科住院医生培训，并移居亚特兰大，在埃默里大学为期四年的基础科学研究跟踪奖学金项目中继续接受心血管疾病方面的培训。然后，他加入了埃默里大学心脏科，担任助理教授。他目前是佐治亚州的执业医生，并获得了美国内科和心血管疾病内科委员会的认证。他将把75%的时间分配给这份申请中提出的研究，25%的时间用于临床心脏病学实践，并在大学环境中教授住院医生和研究员。本项目将重点研究切应力调节的内皮细胞ZBTB46表达在内皮细胞激活中的作用。PI将检验这样的假设，即ZBTB46是一种转录抑制因子，负责防止树突状细胞的免疫激活，在内皮细胞的层流剪切条件下表达，并在扰动的血流中下调，导致内皮细胞的激活。然后，PI将测试剪切敏感MIR的作用，潜在靶向ZBTB46通过扰动流动下调其调节。然后，他将检验这一假设，即内皮细胞中ZBTB46水平的变化(通过下调或过度表达)将改变EC基因的表达，特别是ZBTB46的潜在靶基因，如NR4A1(NFkB抑制剂)、PDGFC，以及NFkB介导的基因，如VCAM1和ICAM1，并影响EC的增殖和小管形成。最后，PI将在动物模型中检验ZBTB46基因敲除导致内皮功能障碍和动脉粥样硬化增加的假设。雷兹万博士将受益于一个导师团队，其中包括著名的血管生物学研究员和专家Jo Hanjoong博士，内科科学家和血管炎症专家W.Robert Taylor博士，免疫学领域的资深研究员Arash Grakoui博士，以及基因表达和表观遗传学方面的资深研究员和专家Jeremy Boss博士。这组导师将为PI提供所需的额外专业知识和培训，以实现他实现科学独立的短期目标，同时加深对ZBTB46在EC激活中作用的理解，从而实现他的长期目标，即成为一名知名的内科科学家，并在开发预防和治疗动脉粥样硬化疾病的新疗法方面取得成功，同时指导年轻的医生和科学家。

 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.