Role of Myeloid Kruppel-like Factor 2 in Vascular Thrombosis

髓系 Kruppel 样因子 2 在血管血栓形成中的作用

• 批准号: 8616228
• 负责人: Lalitha Nayak
• 金额: $ 13.01万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-02 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616228
• 关键词: Advisory Committees; Area; Award; Biological Assay; Biology; Blood; Blood Platelets; Blood Vessels; Bortezomib; Cardiovascular system; Carotid Arteries; Carotid Artery Thrombosis; Cells; Cellular biology; Clinical; Coagulation Process; Complex; Data; Dependency; Development; Development Plans; Dose; EP300 gene; Elements; Embryo; Environment; Foundations; Funding; Future; Goals; Grant; Growth; Hematopoietic; Hemostatic function; Indium; Inflammatory; Injury; Knock-out; Knockout Mice; Kruppel-like transcription factors; Laboratories; Lasers; Lead; Leukocytes; Link; Malignant - descriptor; Malignant Neoplasms; Mentors; Methods; Modeling; Molecular; Molecular Models; Morbidity - disease rate; Multiple Myeloma; Mus; Myelogenous; Myeloid Cells; NF-kappa B; PCAF gene; Pathway interactions; Phenotype; Physicians; Play; Process; Property; Proteasome Inhibitor; Published Comment; Regulation; Relative (related person); Reporter Genes; Reporting; Research; Research Institute; Research Personnel; Research Project Grants; Risk; Role; Rose Bengal; Scientific Advances and Accomplishments; Scientist; Source; Structure; Thromboplastin; Thrombosis; Thrombus; Time; Training; Translating; United States National Institutes of Health; Universities; Zinc Fingers; base; career development; cell type; in vivo; interest; intravital microscopy; molecular modeling; mortality; novel; overexpression; public health relevance; transcription factor

DESCRIPTION (provided by applicant): The application outlines 5 years of mentored research with a formal career development plan under the guidance of Dr. Mukesh Jain, a recognized leader in transcriptional and vascular biology. The applicant, Dr. Lalitha Nayak, a clinical scientist with special interest in hemostasis and thrombosis will also be mentored by an Advisory Committee composed of highly successful, NIH-funded physician scientists at Case Western Reserve University (CWRU) with expertise in her area of research. Although Kruppel-like zinc finger transcription factors play an important role in vascular and hematopoietic cell biology, the role of Kruppel-like factor 2 (KLF2) in regulating thrombotic process in vivo is not defined. Nascent observations by the applicant suggest a critical role for myeloid KLF2 in vascular thrombosis. Utilizing a combination of murine models and molecular/cellular approaches, Dr. Nayak will study the role of myeloid transcription factor Kruppel-like factor 2 (KLF2) in the molecular mechanisms and cellular interactions involved in the dynamic process of thrombosis, a major cause for morbidity and mortality worldwide. Further, Dr. Nayak will extend the studies to examine the antithrombotic effects noted with the widely used anti-myeloma agent, proteasome inhibitor Bortezomib. The specific aims of the proposal include: 1. To investigate the effect of altering myeloid KLF2 on thrombosis: We will use myeloid-specific KLF2 knockout and overexpression mouse lines to conduct vascular thrombosis and examine intercellular interactions during the thrombotic process. 2. To elucidate the molecular mechanisms involved in KLF2's ability to regulate thrombosis: We will employ molecular approaches to elucidate the mechanistic basis of KLF2's ability to alter myeloid pro-thrombotic activity 3. To determine the importance of KLF2 for the antithrombotic effects noted with Bortezomib: We will examine the antithrombotic effect of Bortezomib in myeloid-KLF2 knockout mice to determine the dependency of Bortezomib on KLF2 to produce its antithrombotic effect. This plan is ideally carried out in the Cardiovascular Research Institute (CVRI) at Case Western Reserve University with its distinguished record for training physician-scientists in a rich and collaborative environment. The mentored K08 award will directly advance her scientific development by protecting her effort toward her research project and career development plan. In addition, the career development goal of this project is to help Dr. Nayak transition into an independent investigator with her own laboratory and R01 funding.

描述（由申请人提供）：在穆克什·贾恩（Mukesh Jain）博士的指导下，申请与正式的职业发展计划概述了5年的指导研究，后者是转录和血管生物学的公认领导者。申请人Lalitha Nayak博士（对止血和血栓形成特别感兴趣的临床科学家Lalitha Nayak博士也将受到由Case Western Reserve University（CWRU）的非常成功，由NIH资助的医师科学家组成的咨询委员会（CWRU），并在其研究领域具有专业知识。尽管Kruppel样锌指转录因子在血管和造血细胞生物学中起着重要作用，但未定义的是Kruppel样因子2（KLF2）在体内调节血栓形成过程中的作用。申请人的新生观察表明，髓样KLF2在血管血栓形成中起着至关重要的作用。 Nayak博士利用鼠模型和分子/细胞方法的结合，将研究髓样转录因子Kruppel样因子2（KLF2）在分子机制和细胞相互作用中涉及的动态性血栓形成过程中的作用，这是全球发病率和死亡率的主要原因。此外，Nayak博士将扩展研究，以检查广泛使用的抗肌瘤剂蛋白酶体抑制剂硼替佐米所指出的抗血栓形成作用。该提案的具体目的包括：1。研究改变髓样KLF2对血栓形成的影响：我们将使用髓样特异性的KLF2基因敲除和过表达小鼠线进行血管血栓形成并检查血栓形成过程中细胞间相互作用。 2. To elucidate the molecular mechanisms involved in KLF2's ability to regulate thrombosis: We will employ molecular approaches to elucidate the mechanistic basis of KLF2's ability to alter myeloid pro-thrombotic activity 3. To determine the importance of KLF2 for the antithrombotic effects noted with Bortezomib: We will examine the antithrombotic effect of Bortezomib in myeloid-KLF2敲除小鼠确定硼替佐米对KLF2产生其抗血栓形成效应的依赖性。理想情况下，该计划是在Case Western Reserve University的心血管研究学院（CVRI）中进行的，其杰出的记录是在丰富且协作的环境中培训医师科学家。指导的K08奖将通过保护她在研究项目和职业发展计划上的努力来直接推动她的科学发展。此外，该项目的职业发展目标是通过自己的实验室和R01资金来帮助Nayak博士过渡到独立研究员。