TGF-beta1 activity in the aortic valve

这项提议的目标是将候选人在细胞和组织力学方面的专业知识与 转化生长因子-(31)活性与心血管病理生理的分子机制研究 主动脉瓣硬化症。候选人将由乔安妮·E·墨菲-乌尔里希博士指导，她是一位 转化生长因子-01激活和活性的分子机制，并由Louis J.Dell‘ltalia博士和 心血管生理学、瓣膜疾病和左心室重塑方面的专家。在此期间进行培训 奖项包括授课作业、在导师和合作导师的实验室中轮换，以及定期 会议、研讨会和杂志俱乐部。这种有指导的培训对于应聘者的调查是必不可少的 建议的研究和制定未来NIH在生物医学研究方面的资金建议。 最近，我们发现循环应变和生物活性的转化生长因子-01共同作用于主动脉瓣(AV)叶。 导致主动脉瓣间质细胞(AVICs)协同表型转化为肌成纤维细胞 胶原生成增加，总(潜伏期+生物活性)转化生长因子-β1表达增加11倍 与单独的刺激相比，表明中航工业菌株与转化生长因子-01之间存在积极的相互作用 信号(Merryman，心血管病理学，2007)。然而，机械通过的机制 调节视网膜瘤细胞中转化生长因子-01活性的菌株尚不清楚。我们认为，AV的自然发展 硬化症是由于机械依赖的转化生长因子-(31)信号改变引起的 细胞变形。因此，我们假设转化生长因子-31的合成和/或生物激活的调节是 依赖于细胞株，导致AVICs的表型变化，改变的ECM，和房室硬化。 我们将通过以下目标来检验这一假设： 具体目标1-量化转化生长因子-01的合成和生物激活对生理和 血管内皮细胞单层培养的病理生理环境。 特异靶2-定量检测生理和病理条件下血管内皮细胞转化生长因子-β1的合成和生物活性 病理生理菌株原位培养。 相关性(请参阅说明)： 本研究旨在阐明转化生长因子-31的机械依赖性分子机制及其在血管生成中的作用 主动脉瓣疾病。随着瓣膜病的患病率随着年龄的增长而增加，由于我们的寿命越来越长， 了解这些机制以及如何防止它们是非常重要的。

The goal of this proposal is to synthesize the Candidate's expertise in cell and tissue mechanics with the molecular mechanisms of TGF-(31 activity and cardiovascular pathophysiology to appropriately examine aortic valve (AV) sclerosis. The Candidate will be mentored by Dr. Joanne E. Murphy-Ullrich, an expert in molecular mechanisms of TGF-01 activation and activity, and co-mentored by Dr. Louis J. Dell'ltalia, an expert in cardiovascular physiology, valvular disease, and left ventricle remodeling. Training during this award includes didactic course work, rotations in the laboratories of the mentor and co-mentor, and regular meetings, seminars, and journal clubs. This mentored training is essential for the Candidate to investigate the proposed research and develop future NIH funding proposals in biomedical research. Recently, we found that aortic valve (AV) leaflets exposed to both cyclic strain and bioactive TGF-01 resulted in a synergistic phenotypic shift of aortic valve interstitial cells (AVICs) to myofibroblasts with increased collagen production and 11-fold increase in total (latent + bioactive) TGF-P1 expression compared to either stimulus alone, suggesting positive interactions between AVIC strain and TGF-01 signaling (Merryman, Cardiovascular Pathology, 2007). However, the mechanisms by which mechanical strain regulate TGF-01 activity in the AV are unknown. We propose that the natural progression of AV sclerosis is due to altered mechano-dependent signaling of TGF-(31 by AVICs subjected to increased cellular deformation. Thus, we hypothesize that regulation of TGF-31 synthesis and/or bioactivation is dependent on cellular strain, leading to phenotypic changes of the AVICs, altered ECM, and AV sclerosis. We will test this hypothesis with the following aims: Specific Aim 1- Quantify the dependence of TGF-01 synthesis and bioactivation on physiologic and pathophysiologic strain environments in monolayer culture of AVICs. Specific Aim 2 - Quantify TGF-p1 synthesis and bioactivation from AVICs under physiologic and pathophysiologic strains in situ. RELEVANCE (See instructions): The proposal seeks to elucidate the mechano-dependent molecular mechanisms of TGF-|31 and it'srole in aortic valve disease. As valve disease prevalence grows with age, and due to our increasing lifespan, understanding these mechanisms and how they may be prevented are very important.