The objective of this project is to develop combinatorial libraries of highly defined micro-nanohybrid topographies with tunable elasticity to build an in vitro model of amyloid plaque formation from neural cells for understanding and alleviating Alzheimer's disease (AD). The overall goal is to delineate the molecular mechanism by which transgenic neural cells generate amyloid plaques in a biomimetic microenvironment and discover pharmaceutical targets against AD.
Intellectual Merit: Amyloid plaque formation is a neuropathological hallmark of Alzheimer's disease (AD) which is the most prominent cause of dementia in the elderly. It is caused by the extracellular deposition of aggregated amyloid-beta (A-beta) peptides in the brain. In vivo studies reveal that the amyloid plaque's formation changes the local microenvironment, subsequently leading to neuronal alterations, eventually neurodegeneration. Inhibition of amyloid plaque formation represents a feasible therapeutic target against AD. The current lack of in vitro models of amyloid plaques formed from neural cells greatly limits the progress in seeking strategies to inhibit amyloid plaque formationand identifying therapeutic targets. There is, therefore, a critical need for the development of cell culture technologies in a biomimetic manner that can be reproducibly applied to regulate neural cell behavior to facilitate formation of amyloid plaques for AD research and therapeutic development. Because neural cells as well as A-beta aggregation are highly sensitive to surface properties of the substrate, it is hypothesized that the amyloid plaque formation can be recapitulated by culturing neural cells on highly defined micro-nano-hybrid topographies with tunable elasticity. To test this hypothesis, the PI following specific tasks are proposed: 1) Produce highly defined micro-nano-hybrid topography; 2) Precisely tune the level of elasticity of hydrogels at nanoscale; 3) Engineer combinatorial libraries of micro-nano-hybrid topographies with tunable elasticity to build an in vitro cellular model of amyloid plaque formation. At the completion of this project, the PI expects to have developed the technologies necessary to produce well-defined micro-nano-hybrid topography and to fine tune substrate elasticity at the nanoscale. With these enabling technologies, combinatorial libraries of micro-/nano hybrid topographies with tunable elasticity is engineered to facilitate the establishment of in vitro cellular model of amyloid plaque formation, which is not only crucial to the elucidation of the fundamental of amyloid plaque formation, but will also contribute to understand and alleviate AD.
Broader Impacts: As an indispensable part of this proposal, extensive Education and Outreach activities have been planned to broaden the participation of individuals from underrepresented groups. Graduate and undergraduate students, especially women and minority students will be involved into every aspect of the multidisciplinary research. Graduate students will work on both Engineering and Health Science campuses at WVU, will be taught polymer nanoscience and nanoengineering, and appreciate cell culture and characterization skills at the molecular and cellular levels. Undergraduate students will obtain hands-on research experience to deepen their understanding of scientific principles and to relate classroom knowledge to phenomena they observe in the real world. Moreover, projects comprising teaching modules and lab demonstrations will be developed and integrated into existing outreach events at WVU, especially the weeklong Engineers of Tomorrow summer camp designed to encourage Appalachian area G9-12 students, in particular young women and minorities, to participate in a science or engineering field. Nanobiotechnology will be publicized on Nano Days in Children's Discovery Museum of West Virginia to excite the children and increase public awareness of nanobiotechnology. This project will further collaborative research with health science researchers and foster collaborations with local industries.
