TNF-a and vascular smooth muscle cell phenotypic modulation in cerebral aneurysms

描述(由申请人提供)： 项目摘要/摘要：本申请概述了脑血管/血管内神经外科医生候选人的职业发展计划，重点关注与候选人的临床兴趣相平行的一个极其重要的临床问题--脑动脉瘤。这个项目的直接目标是发展候选人的研究背景和技能，并增加我们对脑动脉瘤生物学的基本理解。长期目标是为候选人的终身职业生涯做好准备，成为一名专注于脑动脉瘤的神经外科医生兼科学家，并通过开发最小或非侵入性治疗方法，最终改善对患有脑动脉瘤的患者的管理。候选人的主要导师是加里·欧文斯博士，他是研究血管平滑肌细胞分化的分子决定因素的领导者。这位候选人还得到了一个由资深科学家和临床科学家(Brian Duling、Neal Kassell、Coleen McNamara和Avril Somlyo博士)组成的咨询委员会的支持，该委员会拥有血管生物学、脑动脉瘤和中风方面的专业知识。所有关键人员在指导学员方面都有丰富的经验。候选人、导师和咨询委员会共同制定了职业发展计划，该计划将：i.)培养候选人在与其临床兴趣相一致的重要领域成功研究的科学背景；2.促进候选人在细胞和分子生物学和遗传学方面获得新的技术技能；在博士后培训和独立调查之间提供一段有指导的过渡期。该计划包括专门的研究时间，出席介绍原创工作的会议，出席学术研讨会、讲座和期刊俱乐部，与导师和咨询委员会举行正式和非正式会议，以及负责进行研究的正式培训。弗吉尼亚大学神经外科为求职者的职业发展提供了最大限度的支持环境。应聘者被聘为神经外科医生兼科学家的全职教师职位，所有资源、基础设施和支持都已到位，以确保成功。候选人拥有新装修和设备齐全的实验室空间，临床同事和支持人员的支持，以确保至少50%的时间被保护用于研究，以及通过医学院和导师和咨询委员会的实验室提供的大量核心设施和共享资源的支持。弗吉尼亚大学为候选人的职业发展提供了理想的环境。这一建议的主要科学焦点涉及肿瘤坏死因子-1在脑血管平滑肌细胞表型转换中的作用及其对脑动脉瘤生物学的影响。尽管成熟的血管平滑肌细胞(SMC)主要与收缩有关，但它们仍具有显著的可塑性，并可能在响应可能产生不良后果的环境提示时发生可逆的表型变化(表型改变)。有明确的证据表明，SMC表型改变在脑血管疾病(如动脉粥样硬化和动脉瘤)的发病机制中起着关键作用。SMC表型调节的特征是转录抑制SMC标记基因(如SM-MHC)和诱导参与基质重塑的基因(如MMPs)。SMC分化的分子控制仍然不完全清楚，也几乎没有被研究应用于脑循环。肿瘤坏死因子-在血管疾病的发病机制中很重要，尽管推测在SMC表型调节中的直接作用尚未被研究。本研究在前期实验的基础上，通过对关键转录因子KLF4的研究，试图阐明肿瘤坏死因子直接诱导体外培养的脑血管SMC表型改变的分子机制，并通过对关键转录因子KLF4的研究，探讨肿瘤坏死因子-1在SMC表型调控中的作用。这项工作将直接应用于中风，中风在北美仍是导致死亡和残疾的第三大原因。 公共卫生相关性： 项目简介：脑动脉瘤在普通人群中相对常见，可能会破裂，产生毁灭性的中风形式。尽管在治疗方面取得了进展，但脑动脉瘤的治疗结果仍然很差，至少部分原因是缺乏对动脉瘤形成、生长和破裂原因的科学见解。我们的研究旨在提高我们对脑动脉瘤形成、生长和破裂的分子机制的理解，并试图为未来的治疗确定新的靶点。

DESCRIPTION (provided by applicant): Project Summary/Abstract: This application outlines a career development plan for the candidate who is a cerebrovascular /endovascular neurosurgeon and focuses on a profoundly important clinical problem, cerebral aneurysms, that parallels the candidate's clinical interests. The immediate goals of this project are to develop the candidate's research background and skills and increase our basic understanding of the biology of cerebral aneurysms. The long-term goals are to prepare the candidate for a life-long career as a neurosurgeon-scientist focused on cerebral aneurysms and to ultimately improve the management of patients harboring cerebral aneurysms through the development of minimally or non-invasive treatments. The candidate's primary mentor is Dr. Gary Owens, who is a leader in the investigation of molecular determinants of vascular smooth muscle cell differentiation. The candidate is also supported by an advisory committee of senior scientists and clinician-scientists (Drs. Brian Duling, Neal Kassell, Coleen McNamara and Avril Somlyo) with expertise in vascular biology, cerebral aneurysms and stroke. All key personnel have vast experience in the mentorship of trainees. Collectively, the candidate, mentor and advisory committee have formulated a career development plan that will: i.) develop the candidate's scientific background for successful research in an important area that parallels his clinical interests; ii.) facilitate the candidate's acquisition of new technical skills in cellular and molecular biology and genetics; and iii.) provide a mentored transition period between postdoctoral training and independent investigation. The plan consists of dedicated research time, attendance at meetings to present original work, attendance of academic seminars, lectures and journal clubs, formal and informal meetings with the mentor and advisory committee, as well as formal training in the responsible conduct of research. The University of Virginia's Department of Neurological Surgery provides a maximally supportive environment for the candidate's career development. The candidate was hired into a neurosurgeon-scientist full-time faculty position and all resources, infrastructure and support are in place to ensure success. The candidate has newly renovated and well equipped laboratory space, the support of clinical colleagues and support staff to ensure at least 50% of his time is protected for research and the support of an abundance of core facilities and shared resources offered through the School of Medicine and through the laboratories of the mentor and advisory committee. The University of Virginia provides the ideal environment for the candidate's career development. The main scientific focus of this proposal concerns the role of TNF- in cerebral vascular smooth muscle cell phenotypic modulation and its impact on the biology of cerebral aneurysms. Although mature vascular smooth muscle cells (SMC) are principally concerned with contraction, they retain remarkable plasticity and may undergo reversible changes in phenotype (phenotypic modulation) in response to environmental cues that can have adverse consequences. There is unequivocal evidence that SMC phenotypic modulation plays a critical role in the pathogenesis of cerebrovascular disease (such as atherosclerosis and aneurysms). SMC phenotypic modulation is characterized by transcriptional repression of SMC-marker genes (such as SM-MHC) and induction of genes involved in matrix remodeling (such as MMPs). The molecular control of SMC differentiation remains incompletely understood and virtually uninvestigated as applied to the cerebral circulation. TNF- is important in vascular disease pathogenesis, although a putative direct role in SMC phenotypic modulation has not been studied. Based upon preliminary experiments that demonstrate that TNF- induces profound phenotypic modulation in cerebrovascular SMC, the present proposal attempts to elucidate the molecular mechanisms by which TNF- directly induces SMC phenotypic modulation in vitro and also determine a potential direct role for TNF- in SMC phenotype modulation in the development and progression of cerebral aneurysms in vivo by focusing on the critical transcription factor, KLF4. This work will have direct translational applications to stroke, which lingers as the third leading cause of mortality and leading cause of disability in North America. PUBLIC HEALTH RELEVANCE: Project Narrative: Brain aneurysms are relatively common in the general population and may rupture producing a devastating form of stroke. Despite advancements in treatment, outcomes for the treatment of brain aneurysms remain poor due, at least in part, to a lack of scientific insight into the cause of aneurysm formation, growth and rupture. Our research aims to improve our understanding of the molecular mechanisms governing brain aneurysm formation, growth and rupture, and also attempts to define novel targets for treatment in the future.