Genetically-altered mechanical homeostasis in central arteries

 描述（由申请人提供）：表明不同基因突变在主动脉疾病中的作用的证据不断积累，在许多情况下，这些突变最终影响壁的机械功能或结构完整性。此外，许多突变优先影响不同的层（例如，中膜内的弹性蛋白相关糖蛋白或平滑肌肌动球蛋白丝）。本项目的目标是量化和比较10种不同突变的影响，这些突变易患主动脉疾病并影响内膜与外膜特性。这些信息，反过来，将提供重要的新的见解偏离不同的机械生物稳态目标的媒体和外膜，并可能激励新的治疗方法。因此，该R 03项目的具体目标是在我们的实验室中挖掘和解释关于小鼠主动脉双轴力学行为的广泛数据库（i）以首次描绘中膜力学行为的差异。 和外膜负荷携带在不同的遗传修饰的小鼠模型和（ii）通知一种新的“生长和重塑”的计算模型，可用于更好地了解如何主动脉试图补偿机械和结构给定的特定基因突变。为此，我们的具体目标是：（1）使用我们最近提出的新的生物力学建模方法，定量和比较10个小鼠模型的主动脉中膜和外膜的双轴应力和相关机械性能，这些小鼠模型具有编码以下基因的突变：弹性蛋白、纤维蛋白-1、纤蛋白-5、胶原蛋白III、胶原蛋白I、血栓蛋白、血管生成素、血管生成素、血管 spondin-2、α平滑肌肌动蛋白、平滑肌肌球蛋白重链、转化生长因子β受体II和潜在转化生长因子结合蛋白3，所有这些都是比较 两个野生型对照（纯背景和混合背景），和（2）扩展，告知和验证我们开发的新的厚壁生长和重塑模型，以了解组成特异性对动脉力学的贡献，但现在将用于更好地描绘层特异性代偿机制，使主动脉适应或导致主动脉适应不良，特别是易受主动脉夹层和破裂的影响。这项建议是在R 03机制下提交的，因为它是一个“小型、自足的研究项目”，将依赖于“对现有数据的二级分析”，但最终会“发展[一种新的]研究方法”。请注意，本提案不是在R21机制下提交的，因为我们不认为它具有高风险。相反，鉴于我们在模型构建以及小鼠力学和机械生物学的各个方面的丰富经验，我们预计不会出现任何技术障碍。相反，我们只需要适度的支持和时间来开发、告知和验证我们认为急需的、高度创新的主动脉生物力学模型，这些模型将更好地揭示主动脉适应性与不断发展的结构脆弱性的遗传基础。

 DESCRIPTION (provided by applicant): Evidence implicating roles of diverse genetic mutations in aortic disease continues to accumulate, and in many cases these mutations ultimately affect the mechanical functionality or structural integrity of the wall. Moreover, many mutations preferentially affect different layers (e.g., elastin-associated glycoproteins or smooth muscle actomyosin filaments within the media). The goal of this project is to quantify and compare effects of ten different mutations that predispose to aortic disease and affect medial versus adventitial properties. This information, in turn, will provide important new insight into deviations from the different mechanobiological homeostatic targets of the media and adventitia and possibly motivate novel therapeutic approaches. The specific goals of this R03 project are, therefore, to mine and interpret an extensive data base in our laboratory on the biaxial mechanical behavior of the murine aorta (i) to delineate, for the first time, differences in medial and adventitial load carrying in diverse genetically modified mouse models and (ii) to inform a novel "growth and remodeling" computational model that can be used to understand better how the aorta attempts to compensate mechanically and structurally given specific genetic mutations. Toward this end, our Specific Aims are: (1) Use our recently proposed novel biomechanical modeling approach to quantify and compare biaxial stresses and associated mechanical properties of the aortic media and adventitia from ten mouse models having mutations in genes that encode: elastin, fibrillin-1, fibulin-5, collagen III, collagen I, thrombo- spondin-2, alpha smooth muscle actin, smooth muscle myosin heavy chain, transforming growth factor beta receptor II, and latent transforming growth factor binding protein 3, all in comparison to two wild type controls (pure and mixed backgrounds), and (2) Extend, inform, and validate a novel thick-walled growth and remodeling model that we developed to understand constituent-specific contributions to arterial mechanics, but which now will be used to delineate better the layer-specific compensatory mechanisms that either enable aortic adaptation or lead to aortic mal-adaptation, particularly vulnerability to aortic dissection and rupture. This proposal is submitted under the R03 mechanism because it is a "small, self-contained research project" that will rely on a "secondary analysis of existing data" and yet result in the "development of [a new] research methodology". Note that this proposal is not submitted under the R21 mechanism because we do not view it as high risk. Rather, given our extensive experience with model building and diverse aspects of mouse mechanics and mechanobiology, we do not anticipate any technical obstacles. Rather, we simply need modest support and time to develop, inform, and validate what we feel are much needed, highly innovative models of aortic biomechanics that will better reveal the genetic basis of aortic adaptivity versus evolving structural vulnerability.