Genetically-altered mechanical homeostasis in central arteries

 描述(申请人提供)：涉及多种基因突变在主动脉疾病中作用的证据继续积累，在许多情况下，这些突变最终影响血管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，弹性蛋白相关的糖蛋白或介质中的平滑肌肌动球蛋白细丝)。该项目的目标是量化和比较10种不同突变的效果，这些突变易导致主动脉疾病，并影响内膜和外膜的特性。这些信息，反过来，将提供重要的新见解偏离不同的机械生物学动态平衡的目标的媒体和外膜，并可能激励新的治疗方法。因此，R03项目的具体目标是挖掘和解释我们实验室中关于小鼠主动脉双轴力学行为的广泛数据库(I)第一次描绘出内侧动脉的差异。 我们的目标是：(I)在不同的转基因小鼠模型中研究和携带外膜负荷；(Ii)提供一种新的“生长和重塑”计算模型，该模型可以用来更好地理解给定特定基因突变时，主动脉如何试图从机械和结构上进行补偿。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来量化和比较10个具有以下编码基因突变的小鼠模型的主动脉中膜和外膜的双向应力和相关的力学特性：弹性蛋白、纤维蛋白-1、纤维蛋白-5、III型胶原、I型胶原、血栓- Spin2、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和潜伏的转化生长因子结合蛋白3，所有这些都是比较的 两个野生型对照(纯背景和混合背景)，以及(2)扩展、告知和验证我们开发的新的厚壁生长和重塑模型，该模型是为了了解成分对动脉力学的特定贡献而开发的，但现在将被用来更好地描述使主动脉适应或导致主动脉适应不良的层特异性代偿机制，特别是对主动脉夹层和破裂的易感性。这项提案是在R03机制下提交的，因为它是一个“小型、自给自足的研究项目”，将依赖于“对现有数据的二次分析”，但结果是“开发了一种新的研究方法”。请注意，这项提案不是根据R21机制提交的，因为我们不认为它是高风险的。相反，鉴于我们在建模方面的丰富经验，以及对老鼠力学和机械生物学的不同方面，我们预计不会有任何技术障碍。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迫切需要的、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演变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.