TGF-beta1 activity in the aortic valve

描述（由申请人提供）：本课题的目的是将候选人在细胞和组织力学方面的专业知识与TGF-(31)活性的分子机制和心血管病理生理结合起来，适当地检查主动脉瓣（AV）硬化。候选人将由TGF-01激活和活性分子机制专家Joanne E. Murphy-Ullrich博士指导，并由心血管生理学、瓣膜疾病和左心室重塑专家Louis J. Dell' italia博士共同指导。该奖项期间的训练包括教学课程、导师和联合导师在实验室的轮转、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生物医学研究的资助提案至关重要。

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.