This is an application filed in response to RFA-DC-07-005 """"""""Short-Term Interdisciplinary Career Enhancement Awards for Neuro-degeneration Research"""""""". The proposed candidate is James P. Bennett, Jr. M.D., Ph.D., who is currently Arthur and Margaret Ebbert Professor of Medical Science and Professor of Neurology at the University of Virginia (UVA). Dr. Bennett's entire 23-year academic career as a translational physician-scientist faculty member has been devoted to neurodegenerative research. He has held multiple NIH awards, beginning with a RCDA from 1985-1990, with subsequent awards of four R01 grants, two Program Projects and the P50 Udall Parkinson's Center at UVA that recently was competitively renewed through 2010. He has had significant translational output and presently holds a Physician-Sponsor IND for a novel neuroprotective drug and is PI for a STTR grant to develop mitochondrial gene therapy. He is a nationally known investigator into the mitochondrial pathobiology of neurodegenerative diseases. In the proposed career enhancement plan Dr. Bennett will learn how to derive neuroepithelial precursor (NEP) cells from NIH-approved human embryonic stem cells (hESC). He will learn this technique by attending a NIH-sponsored workshop followed by working closely with Dr. Raj Rao, a bioengineer on the faculty at Virginia Commonwealth University (VCU) and expert in neural stem cell biology. The goal of this project is for Dr. Bennett to create novel cell lines to serve as improved models of Alzheimer's (AD) and Parkinson's (PD) diseases by using a novel mitochondrial DNA (mtDNA) transfer technology to transfer AD and PD mtDNA into NEP cells depleted of their own mtDNA. These novel cell lines will allow exploration of unique disease pathogenesis hypotheses and will also serve as excellent drug screening platforms. The Award will allow Dr. Bennett to devote a 65% effort to this goal over 12 months of support. The precise causes of premature nerve cell death in Alzheimer's and Parkinson's patients' brains remain unknown. This award will support the creation of novel human nerve cells that carry mitochondrial genes from Alzheimer's and Parkinson's patients. These nerve cell lines can help scientists understand why nerve cells die prematurely in these diseases and can be used to develop new drugs to prevent cell death. ? ?
|Iyer, S; Xiao, E; Alsayegh, K et al. (2012) Mitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors. Gene Ther 19:469-75|
|Thomas, Ravindar R; Khan, Shaharyar M; Portell, Francisco R et al. (2011) Recombinant human mitochondrial transcription factor A stimulates mitochondrial biogenesis and ATP synthesis, improves motor function after MPTP, reduces oxidative stress and increases survival after endotoxin. Mitochondrion 11:108-18|
|Keeney, Paula M; Quigley, Caitlin K; Dunham, Lisa D et al. (2009) Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson's disease cell model. Hum Gene Ther 20:897-907|
|Borland, M Kathleen; Mohanakumar, K P; Rubinstein, Jeremy D et al. (2009) Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues. Biochim Biophys Acta 1792:68-74|
|Keeney, Paula M; Dunham, Lisa D; Quigley, Caitlin K et al. (2009) Cybrid models of Parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships. Exp Neurol 220:374-82|
|Iyer, Shilpa; Alsayegh, Khaled; Abraham, Sheena et al. (2009) Stem cell-based models and therapies for neurodegenerative diseases. Crit Rev Biomed Eng 37:321-53|
|Iyer, Shilpa; Thomas, Ravindar R; Portell, Francisco R et al. (2009) Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression. Mitochondrion 9:196-203|