PECASE: Adhesion and Mechanics of Normal and Dystrophic Muscle Cells - A Cellular Engineering Basis for Gene Therapy

9876328 discher为了实现组织的完整性和弹性，细胞必须有足够的能力与组织结构或基质粘附和变形。这项NSF-CAREER提案的一个总体目标是开发细胞粘附的新方法，特别关注肌肉萎缩症（MD）。第二个目标是在更广泛的、新兴的细胞和分子工程领域创造新的教育机会和资源。这些研究和教育计划的整合预计将促进将工程研究转移到临床和工业部门的伙伴关系，为越来越多代表性不足的少数民族和妇女在工程科学方面取得成就做好准备，并使广泛的受众接触到发现的兴奋。MD是一种常见的、使人衰弱的、通常是致命的遗传疾病，其基因治疗的迅速发展为详细研究肌肉细胞粘附提供了动力。尽管细胞膜上的粘附和细胞骨架蛋白与这些疾病有松散的关系，但就功能的定量方面而言，我们所知甚少。工业和组织工程师可能感兴趣的新型、有图案的蛋白质基质将首先被设计成几何上控制肌肉细胞的生长和分化。在这些确定的底物上生长的单个细胞将被强行从底物上剥离。各种光学显微镜将允许在纳米到微观尺度上进行定量分析。几种营养不良型肌肉细胞的反应将与正常细胞进行比较，目的是补充和激励正在出现的基因治疗努力。多尺度的理论模型，包括不可扩展的胶带剥离模型和基于分子力学的“分子”元素模型，将致力于推进细胞膜力学和粘附的结构-功能假设。一个补充的教育计划，在细胞和分子工程的更广泛的领域提出了不同的学术水平，以及为一般公众。实验室实习项目将为来自不同背景的本科生提供指导。针对不同受众的新的动手细胞和分子工程实验室练习将补充本科和研究生阶段工程课程的重点课程，一个公共访问网站将专门用于细胞和分子工程教育（http://www.seas.upenn.edu/ ~discher/ cme.html）。

9876328DischerTo achieve tissue integrity and resilience, cells must have sufficient ability to adhere and deform with tissue structures or matrices. One overall goal of this NSF-CAREER proposal is to develop novel approaches to cell adhesion, with a particular focus on muscular dystrophy (MD). A second goal is to create new educational opportunities and resources in the broader, emerging area of cell and molecular engineering. Integration of these research and education plans is expected to promote partnerships for the transfer of engineering research to both the clinical and industrial sectors, to prepare an increased number of underrepresented minorities and women for achievement in engineering science, and to expose a broad-based audience to the excitement of discovery.Motivation for detailed study of muscle cell adhesion is provided by burgeoning treatments of gene therapy for MD, a collection of common, debilitating, and often fatal genetic disorders. Though adhesion and cytoskeletal proteins at the cell membrane are loosely implicated in these disorders, very little is known in terms of quantitative aspects of function. Novel, patterned protein substrates -- of potential interest to industry and tissue engineers -- will first be engineered to geometrically control the growth and differentiation of muscle cells. Individual cells grown on these defined substrates will then be forcibly peeled from the substrates. Various optical microscopies will allow quantitative analysis at the nano- to micro- scales. The responses of several dystrophic-type muscle cells will be compared to normal cells with the intent of complementing and motivating gene therapy efforts which are emerging. Theoretical models at multiple scales, including an inextensible tape-peeling model and "molecular" element models rooted in molecular mechanics, will be pursued to advance structure-function hypotheses on cell membrane mechanics and adhesion.A complementary educational plan in the broader area of cell and molecular engineering is proposed for various academic levels as well as for the general public. An in-lab internship program will enable the mentoring of undergraduates from diverse backgrounds. New hands-on cell and molecular engineering laboratory exercises for diverse audiences will supplement focused course offerings at undergraduate and graduate levels of the engineering curriculum, and a public-access internet site will be dedicated to Education in Cell and Molecular Engineering (http://www.seas.upenn.edu/ ~discher/ cme.html).