EPIGENETIC OPTIMIZATION OF NEURONAL CELL REPLACEMENT STRATEGIES USING INDUCED PLURIPOTENT STEM CELLS (IPSCS)

Exposure to blast, bullets and shrapnel, vehicle crashes and falls significantly elevate the risk of traumatic brain injury (TBI) in military personnel. TBI can lead to a spectrum of functional deficits that range from impairments in motor and sensory behaviors to loss of memory, poor executive functioning, as well as psychological problems such as post-traumatic stress disorder (PTSD) and social dislocation. Despite the individual, social and economic burdens of TBI, no therapies exist to restore many of the brain functions lost to injury. Stem cell transplantation offers the greatest potential in the restoration of brain function. The most promising stem cell approach is to reverse engineer somatic cells to induce pluripotent stem cells (iPSCs) for directed neuronal differentiation and transplantation. This approach permits the grafting of cells derived from each patient, thereby reducing stem cell rejection by the host¿s immune system. A major goal in developing neuronal stem cell-programmed iPSCs (NSC-iPSC) treatment strategies is to ensure the successful functional integration of grafted cells. We propose this goal can be achieved by manipulating the epigenome of NSC-iPSCs. The epigenome is the chemical properties of chromatin DNA and histone proteins that control gene function. The epigenome is an attractive therapeutic target as it can be manipulated by small molecule compounds to effect widespread changes in gene expression. Our proposal focuses on the epigenetic regulator Kdm5b. This focus is based on our preliminary data revealing Kdm5b inhibition results in epigenetic-associated changes in gene expression that increase the development of neurons from neural stem cells (NSCs). Accordingly, our hypothesis is that Kdm5b inhibition will increase the survival, distribution and integration of NSC-iPSCs grafted into the brain. We propose to test this hypothesis by determining the effects of Kdm5b inhibition on the fate of NSC-iPSCs in culture and in mouse brain transplantation studies. The successful completion of this project will provide important data in the development of protocols to optimize cell replacement strategies for the successful treatment of TBI.