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)：申请表概述了在转录和血管生物学领域公认的领导者Mukesh Jain博士的指导下，为期5年的有指导的研究和正式的职业发展计划。申请者Lalitha Nayak博士是一位对止血和血栓形成特别感兴趣的临床科学家，她还将接受一个咨询委员会的指导，该委员会由凯斯西储大学(CWRU)非常成功的NIH资助的内科科学家组成，他们在她的研究领域拥有专业知识。尽管Kruppel样锌指转录因子在血管和造血细胞生物学中发挥着重要作用，但Kruppel样因子2(KLF2)在体内调节血栓形成过程中的作用尚不清楚。申请人的初步观察表明，髓系KLF2在血管血栓形成中起着关键作用。Nayak博士将结合小鼠模型和分子/细胞方法，研究髓系转录因子Kruppel-like factor2(KLF2)在血栓形成动态过程中的分子机制和细胞相互作用中的作用。血栓形成是全球发病率和死亡率的主要原因。此外，纳亚克博士还将进一步研究广泛使用的抗骨髓瘤药物蛋白酶体抑制剂Bortezomib的抗血栓作用。该提案的具体目的包括：1.研究改变髓系KLF2对血栓形成的影响：我们将使用髓系特异性KLF2基因敲除和过表达的小鼠系来引导血管血栓形成，并检测血栓形成过程中细胞间的相互作用。2.阐明KLF2的S调节血栓形成的分子机制：我们将利用分子方法阐明KLF2的S改变髓系血栓前活性的机制。3.确定KLF2在Bortezomib抗血栓作用中的重要性：我们将在髓系KLF2基因敲除的小鼠中检测Bortezomib的抗血栓作用，以确定Bortezomib对KLF2产生抗血栓作用的依赖性。该计划理想地在凯斯西储大学心血管研究所(CVRI)实施，该研究所在丰富和协作的环境中培训内科科学家方面有着卓越的记录。K08导师奖将通过保护她在研究项目和职业发展计划上的努力，直接推动她的科学发展。此外，该项目的职业发展目标是帮助纳亚克博士利用自己的实验室和R01资金过渡到一名独立的研究员。