Promotion of tissue engineering angiogenesis via analysis of cellular decision-making processes in response to mechanical and biomolecular cues

主要研究者：Masters，Kristyn提案编号：1401584机构：威斯康星大学麦迪逊分校通过分析响应于机械和生物分子的细胞决策过程促进组织工程血管生成由于仅扩散不足以在组织中提供足够的营养输送和废物清除，因此认为血管供应对于维持厚度大于0.2 mm的大多数组织的活力和功能是必要的。在生物材料支架中不能促进这种血管供应的形成仍然是产生健康的工程组织的主要障碍。该项目中提出的工作将提供计算和实验信息，以帮助设计允许增强血管形成（称为血管生成）的支架环境。预计拟议的研究将确定最能促进血管生成的特定支架设计参数，并研究将不良血管生成支架环境转换为更好地支持血管生成的环境的药物策略。总的来说，这项工作的目的是产生信息，帮助克服目前面临的最重要的障碍，建设可行的工程组织。此外，这项工作为对其他细胞和组织类型进行类似的研究奠定了基础;这种关于控制和预测细胞行为的扩展信息库在许多应用中将是非常宝贵的。该提案由化学、生物工程、环境和运输系统部门的生物医学工程项目和材料研究部门的生物材料项目共同资助。血管生成过程可能受到许多细胞外影响的指导，例如可溶性生长因子、固定化生长因子、细胞外基质（ECM）成分和机械力。虽然内皮细胞（EC）对这些单独刺激的血管生成反应已被表征，但对细胞如何解释和响应这些信号的组合知之甚少。此外，单独鉴定最佳血管生成培养条件对于所有组织工程应用将是不够的，因为特定于给定靶组织的其它物理和生物学要求将限制支架设计的许多要素。了解这些信号调节血管生成的方式对于在需要血管生成的应用中取得进展至关重要，例如组织工程。该建议是基于这样的假设，即血管生成可以促进组织工程应用中通过操纵细胞的决策过程，发生在响应于交付的组合微环境的线索。 这一假设将通过综合实验和计算研究方法来解决，特别是通过1）分析EC如何响应生长因子、机械和ECM线索的组合，2）确定EC感知、解释和响应这些线索的信号传导过程，3）构建与信号传导过程和血管生成结果相关的计算模型，以及4）应用该模型来实验性地操纵血管生成反应。最终，拟议的研究将有助于更好地理解和预测细胞决策过程，可用于识别支持血管生成的支架条件，更广泛地告知组织工程支架设计原则，并开发药物方法来促进限制血管生成的支架中的血管生成。

PI: Masters, KristynProposal Number: 1401584Institution: University of Wisconsin-Madison Title: Promotion of tissue engineering angiogenesis via analysis of cellular decision-making processes in response to mechanical and biomolecular cuesBecause diffusion alone is not sufficient to provide adequate nutrient delivery and waste removal in tissues, a blood vessel supply is considered necessary to maintain the viability and function of most tissues thicker than 0.2 mm. Currently, the inability to promote the formation of such a blood vessel supply in biomaterial scaffolds remains a major obstacle in the creation of healthy engineered tissues. The work proposed in this project will provide both computational and experimental information to help the design of scaffold environments that permit enhanced blood vessel formation (known as angiogenesis). Proposed studies are expected to identify specific scaffold design parameters that best promote angiogenesis, as well as investigate pharmaceutical strategies for switching poorly angiogenic scaffold environments into ones that better support angiogenesis. Overall, this work is intended to yield information that helps overcome the most significant obstacle currently facing the construction of viable engineered tissues. Additionally, this work sets the stage to perform similar investigations with other cell and tissue types; such an expanded library of information with respect to controlling and predicting cellular behaviors would be invaluable in numerous applications. This proposal is co-funded by the Biomedical Engineering Program in the Chemical, Bioengineering, Environmental and Transport Systems Division, and by the Biomaterials Program in the Division of Materials Research.The process of angiogenesis may be guided by numerous extracellular influences, such as soluble growth factors, immobilized growth factors, extracellular matrix (ECM) components, and mechanical forces. While the angiogenic response of endothelial cells (ECs) to these individual stimuli has been characterized, little is known on how cells interpret and respond to combinations of these signals. Moreover, the identification of optimally angiogenic culture conditions alone will not be sufficient for all tissue engineering applications, as the other physical and biological requirements specific to a given target tissue will constrain many elements of the scaffold design. Understanding the manner in which these cues regulate angiogenesis is critical in making advances in applications that require angiogenesis, such as tissue engineering. This proposal is based on the hypothesis that angiogenesis can be promoted in tissue engineering applications via manipulation of cellular decision-making processes that occur in response to the delivery of combinations of microenvironmental cues. This hypothesis will be addressed by an integrated experimental and computational research approach and specifically by 1) analyzing how ECs respond to combinations of growth factor, mechanical, and ECM cues, 2) determining the signaling processes by which ECs sense, interpret, and respond to these cues, 3) building a computational model relating signaling processes and angiogenic outcomes, and 4) applying this model to experimentally manipulate angiogenic responses. Ultimately, the proposed studies will help to better understand and predict cellular decision-making processes that could be used to identify scaffold conditions that support angiogenesis, more broadly inform tissue engineering scaffold design principles, and develop pharmaceutical approaches to promote angiogenesis in scaffolds that restrict angiogenesis.