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

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连和变形。这个NSF职业提案的一个总体目标是开发新的细胞黏附方法，特别关注肌营养不良症(MD)。第二个目标是在更广泛、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有望促进将工程研究转移到临床和工业部门的合作伙伴关系，为更多未被充分代表的少数族裔和妇女在工程科学方面的成就做好准备，并让广泛的受众接触到发现的兴奋。MD的基因治疗是一种常见的、衰弱的、往往是致命的遗传病，它的蓬勃发展为详细研究肌肉细胞粘连提供了动力。尽管细胞膜上的黏附和细胞骨架蛋白与这些疾病有松散的联系，但人们对功能的定量方面知之甚少。工业和组织工程师可能感兴趣的新型图案化蛋白质底物将首先进行工程设计，以几何方式控制肌肉细胞的生长和分化。然后，在这些定义的基板上生长的单个细胞将被强制从基板上剥离。各种光学显微镜将允许在纳米到微米尺度上进行定量分析。几个营养不良类型的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。将寻求多尺度的理论模型，包括不可扩展的胶带剥离模型和植根于分子力学的“分子”元素模型，以推进关于细胞膜力学和粘附性的结构-功能假说。在更广泛的细胞和分子工程领域，为不同的学术水平和普通公众提出一个补充的教育计划。实验室实习计划将为来自不同背景的本科生提供指导。面向不同受众的新的动手细胞和分子工程实验室练习将补充工程课程本科生和研究生水平的重点课程，一个公共访问的互联网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).