Efforts to investigate the pathophysiology of human diseases such as Alzheimer's disease (AD) are hampered by the lack of genuine in-vitro models. Stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities by providing specific/ personalized models for studying human disease, and personalized renewable source of cells for practical autologous cell therapies and regenerative medicine applications, that avoid immune rejection. The possibility of using iPS cells as a tool for development of such AD patient specific model systems, however, remains at best challenging and still a clear unmet need due to the shortcomings in this field. Studies outlined in this proposal are designed to explore resolution of this unmet need with the ultimate goal of developing AD patient specific cells as a tool for study of the pathophysiology of this disease and drug testing. We propose to use a novel robust and efficient iPS methodology which employs a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSTM) cells, eliminating the need for any exogenous gene transduction (i.e. a major impediment of iPS methodologies described by others). In this Phase I study, feasibility of this approach will be demonstrated via CiPS derivation of a small number of AD patients', skin biopsy, fibroblasts samples. These CiPS patient specific cells will be obtained without any abnormal and permanent modifications to the cellular and molecular machinery typically observed by other DNA vector induced iPS methodologies. Tools and technologies developed by the proposed study have direct applications to the study of molecular and cellular pathways of other neurodegenerative and age related diseases. PUBLIC HEALTH RELEVANCE: Efforts to investigate the pathophysiology of human diseases such as Alzheimer's disease are hampered by the lack of genuine in-vitro models. Medical and biotechnological potential of stem cells have been recognized as unprecedented opportunities for understanding basic disease mechanisms, screens for drug discovery, and tissue engineering for degenerative diseases and crippling injuries. In particular, stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies and regenerative medicine applications, that avoid immune rejection. We propose to use a novel robust and efficient iPS methodology that uses a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSTM) cells, which eliminates the need for any exogenous gene transduction. Patient specific pluripotent cells are derived, without any abnormal and permanent modifications to the cellular and molecular machinery (i.e. a major shortcoming of all other DNA vector mediated iPS inductions reported to date). Tools and technologies developed by the proposed study have direct applications to the study of molecular and cellular pathways of other neurodegenerative and age related diseases.