TGF-beta1 activity in the aortic valve

主动脉瓣中的 TGF-β1 活性

• 批准号: 7901192
• 负责人: WILLIAM D MERRYMAN
• 金额: $ 3.5万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901192
• 关键词: aortic valve; human TGFB1 protein

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本提案的目标是综合候选人在细胞和组织力学方面的专业知识以及TGF-β 1活性和心血管病理生理学的分子机制，以适当检查主动脉瓣（AV）硬化。候选人将由Joanne E博士指导。Murphy-Ullrich博士是TGF-01激活和活性分子机制的专家，并由Louis J. Dell'Italia博士共同指导，Louis J. Dell' Italia博士是心血管生理学、瓣膜疾病和左心室重塑方面的专家。该奖项期间的培训包括教学课程工作，导师和共同导师的实验室轮换，以及定期会议，研讨会和期刊俱乐部。这种指导培训对于候选人调查拟议的研究和制定未来NIH在生物医学研究中的资助提案至关重要。 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）向肌成纤维细胞的协同表型转变，胶原蛋白产生增加，总胶原蛋白增加11倍。与单独刺激相比，（潜伏+生物活性）TGF-β 1表达，表明AVIC菌株与TGF-β 1信号传导之间存在正相互作用（Merryman，Cardiovascular Pathology，2007）。然而，机械应变调节AV中TGF-01活性的机制尚不清楚。我们认为AV硬化的自然进展是由于AVIC受到细胞变形增加而改变了TGF-β 1的机械依赖性信号传导。因此，我们假设TGF-β 1合成和/或生物活化的调节依赖于细胞应变，导致AVIC的表型变化、ECM改变和AV硬化。我们将检验这一假设，目的如下： 具体目标1 -定量AVIC单层培养物中TGF-01合成和生物活化对生理和病理生理应变环境的依赖性。 具体目标2 -在原位生理和病理生理菌株下定量AVIC的TGF-β 1合成和生物活化。