To 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 (www.seas.upenn.edu/ ~discher/ cme.html).
