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

脑动脉瘤中TNF-a和血管平滑肌细胞表型调节

基本信息

批准号：
8145719
负责人：
AARON S DUMONT
金额：
$ 17.21万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8145719
关键词：
Acetylation Actins Advisory Committees Aneurysm Angioplasty Area Atherosclerosis Binding Binding Proteins Binding Sites Biology Blood Pressure Blood Vessels Blood flow Bone Marrow Bone Marrow Cells Brain Aneurysms CCL2 gene Caliber Carotid Arteries Carotid Artery Injuries Cell Differentiation process Cell Line Cells Cerebral Aneurysm Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Characteristics Clinical Core Facility Cues Cytoskeletal Gene Data Dermal Development Development Plans Differentiation Antigens Elements Ensure Environment Epigenetic Process Evaluation Exhibits Faculty Fibroblasts Future Gel Gene Activation Gene Expression General Population Genes Goals Growth Human Resources Hybrids Hypertension In Vitro Incidence Inflammation Inflammatory Injury Intracranial Aneurysm Investigation Journals Knockout Mice Kruppel-like transcription factors Laboratories LacZ Genes Lead Life Ligation MMP3 gene Matrix Metalloproteinases Mediating Mediator of activation protein Mentors Mentorship Messenger RNA Methylation Modeling Molecular Molecular Genetics Molecular and Cellular Biology Mus Mutate Neurosurgeon Neurosurgical Procedures North America Pathogenesis Patients Phenotype Platelet Factor 4 Platelet-Derived Growth Factor Play Pluronics Positioning Attribute Promoter Regions Proteins Regulation Relative (related person)Reporter Repression Research Research Infrastructure Research Support Resource Sharing Resources Reverse Transcriptase Polymerase Chain Reaction Role Rupture Scientist Senior Scientist Serum Response Factor Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Somatic Cell Source Stem cells Stress Stroke Stromelysin 1 Structure TNF gene Tamoxifen Testing Time Training Transgenes Transgenic Mice Treatment outcome Universities Vascular Cell Adhesion Molecule-1 Vascular Diseases Virginia Western Blotting Work Yeasts abstracting adverse outcome base career career development cerebrovascular chromatin immunoprecipitation cohort cytokine disability embryonic stem cell experience gene induction gene repression hemodynamics histone modification improved in vivo insight interest irradiation lectures mature animal medical schools meetings migration mortality mutant myocardin neointima formation novel post-doctoral training promoter public health relevance reconstitution regional difference renal artery research study response responsible research conduct restenosis skills success transcription factor vascular bed

项目摘要

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.

描述（由申请人提供）：项目摘要 /摘要：该应用程序概述了候选人的职业发展计划，该候选人是脑血管 /血管内神经外科医生，重点介绍了一个非常重要的临床问题，即脑动脉瘤，与候选人的临床兴趣相似。该项目的直接目标是发展候选人的研究背景和技能，并提高我们对脑动脉瘤生物学的基本理解。长期的目标是为终身职业的候选人做好准备，作为一个致力于脑动脉瘤的神经科学家，并最终通过开发微小或非侵入性治疗来改善具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（Gary Owens）博士，他是研究血管平滑肌细胞分化分子决定因素的领导者。该候选人还得到了高级科学家和临床医生的咨询委员会（Brian Duling博士，Neal Kassell博士，Coleen McNamara和Avril Somlyo），具有血管生物学，大脑动脉瘤和中风方面的专业知识。所有关键人员在受训者的指导中都有丰富的经验。总体而言，候选人，导师和咨询委员会制定了一项职业发展计划：i。 ii。）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；和iii。）在博士后培训和独立调查之间提供指导的过渡期。该计划包括专门的研究时间，参加会议，以介绍原始工作，学术研讨会，讲座和期刊俱乐部的出席，与导师和咨询委员会的正式和非正式会议以及负责任的研究进行正式培训。弗吉尼亚大学的神经系统外科系为候选人的职业发展提供了最大的支持环境。候选人被聘为神经外科医生的全职教师职位以及所有资源，基础设施和支持，以确保成功。候选人已经进行了新装修且设备齐全的实验室空间，临床同事的支持和支持人员，以确保他的至少50％的时间受到研究的保护，并通过医学院和通过导师和咨询委员会的实验室提供了丰富的核心设施和丰富的核心设施和共享资源。弗吉尼亚大学为候选人的职业发展提供了理想的环境。该提案的主要科学重点是TNF-在脑血管平滑肌细胞表型调节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，但它们保留了显着的可塑性，并且可能会对可能带来不利后果的环境线索进行表型（表型调节）的可逆变化（表型调节）。有明确的证据表明，SMC表型调节在脑血管疾病的发病机理（例如动脉粥样硬化和动脉瘤）中起着至关重要的作用。 SMC表型调制的特征是对SMC标记基因（例如SM-MHC）的转录抑制以及涉及基质重塑（例如MMP）的基因的诱导。 SMC分化的分子控制仍然不完全理解，并且实际上未经评估，如应用于大脑循环。 TNF-在血管疾病发病机理中很重要，尽管尚未研究SMC表型调节中的推定直接作用。基于初步实验，该实验表明TNF-在脑血管SMC中诱导了深刻的表型调节，本提案试图阐明TNF-直接在Intro中直接诱导SMC表型调节的分子机制，并在SMC中促进SMC的潜在调制，并确定SMC在SMC中的潜在直接作用。关于关键转录因子KLF4。这项工作将直接转化为中风，这是北美死亡率的第三个主要原因和主要原因。公共卫生相关性：项目叙述：大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步，但至少由于缺乏对动脉瘤形成，生长和破裂的原因缺乏科学见解，脑动脉瘤的治疗结果仍然很差。我们的研究旨在提高我们对管理大脑动脉瘤形成，生长和破裂的分子机制的理解，并尝试定义未来治疗的新目标。