Role of Myeloid Kruppel-like Factor 2 in Vascular Thrombosis

描述（由申请人提供）：该申请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，5年的指导研究和正式的职业发展计划。申请人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，也将由凯斯西储大学（CWRU）的非常成功的美国国立卫生研究院资助的医师科学家组成的咨询委员会指导，他们在她的研究领域具有专业知识。虽然kruppel样锌指转录因子在血管和造血细胞生物学中发挥重要作用，但kruppel样因子2 （KLF2）在体内调节血栓形成过程中的作用尚不明确。申请人的初步观察表明髓系KLF2在血管血栓形成中起关键作用。利用小鼠模型和分子/细胞方法的结合，Nayak博士将研究髓系转录因子kruppel样因子2 （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，Nayak博士将扩展研究，以检查广泛使用的抗骨髓瘤药物，蛋白酶体抑制剂硼替佐米的抗血栓作用。该提案的具体目标包括：1。为了研究改变髓系KLF2对血栓形成的影响：我们将使用髓系特异性KLF2敲除和过表达小鼠系进行血管血栓形成，并检查血栓形成过程中的细胞间相互作用。2. 为了阐明KLF2调节血栓形成能力的分子机制：我们将采用分子方法来阐明KLF2改变髓系促血栓活性能力的机制基础3。为了确定KLF2对硼替佐米抗血栓作用的重要性：我们将检查硼替佐米在髓系KLF2敲除小鼠中的抗血栓作用，以确定硼替佐米对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的心血管研究所（CVRI）进行，该研究所在丰富和协作的环境中培养医生科学家方面有着杰出的记录。K08导师奖将保护她的研究项目和职业发展计划，直接促进她的科学发展。此外，该项目的职业发展目标是帮助Nayak博士过渡到拥有自己的实验室和R01基金的独立研究者。

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.