TGF-beta1 activity in the aortic valve

本提案的目标是将候选人在细胞和组织力学方面的专业知识与 TGF-β 1活性的分子机制和心血管病理生理学，以适当地检查 主动脉瓣硬化。候选人将由Joanne E博士指导。墨菲-乌尔里希是一位 TGF-01激活和活性的分子机制，并由Louis J. Dell'Italia博士共同指导， 心血管生理学、瓣膜疾病和左心室重塑方面的专家。培训期间， 奖励包括教学课程工作，导师和共同导师实验室的轮换，以及定期 会议、研讨会和期刊俱乐部。这种指导式培训对于候选人进行调查至关重要 建议的研究和发展未来NIH在生物医学研究方面的资助建议。 最近，我们发现暴露于周期性应变和生物活性TGF-01的主动脉瓣（AV）小叶 导致主动脉瓣间质细胞（AVIC）协同表型转变为肌成纤维细胞， 胶原蛋白生成增加，总（潜伏+生物活性）TGF-β 1表达增加11倍 与单独的刺激相比，表明AVIC株与TGF-01之间存在正相互作用 信号传导（Merryman，Cardiovascular Pathology，2007）。然而，机械化的机制 调节AV中TGF-01活性的菌株是未知的。我们认为AV的自然进展 硬化是由于AVIC的TGF-β 1的机械依赖性信号传导改变， 细胞变形因此，我们假设TGF-31合成和/或生物活化的调节是 依赖于细胞应变，导致AVIC的表型变化、改变的ECM和AV硬化。 我们将检验这一假设，目的如下： 具体目的1-定量TGF-β 1合成和生物活化对生理和生理学特性的依赖性， AVIC单层培养中的病理生理应变环境。 具体目的2 -在生理和生理条件下定量来自AVIC的TGF-β 1合成和生物活化 原位病理生理菌株。 相关性（参见说明）： 该提案旨在阐明TGF-β 1的机械依赖性分子机制。|31和它的作用， 主动脉瓣疾病由于瓣膜疾病的患病率随着年龄的增长而增加，并且由于我们的寿命增加， 了解这些机制以及如何预防这些机制非常重要。

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.