The presence of endogenous neural progenitor cells in the adult brain has prompted a search for ways to stimulate their proliferation and migration. The ability to manipulate neural stem cells in this way has many clinical implications for neural repair as new neurons that are directed towards injured brain sites to replace those that have died. A better understanding of the extrinsic and intrinsic mechanisms underlying this restorative response is vital for enhancing the proliferation and migration of NSCs following stroke. The overall goal of this project is to examine the functional relevance of interactions between an important class of extrinsic factors, the chemokines, and the cellular Ca2+ signaling machinery for neurogenesis in the normal and stroke injured brain. Chemokines are secreted regulatory factors that play an essential role in neurogenesis and progenitor migration. As a multifunctional second messenger, Ca2+ activates distinct genetic programs that regulate many processes such as the proliferation of NSCs, migration, and differentiation into mature neurons and glia. However, how NSCs generate Ca2+ signals in response to chemokines and other regulatory factors remains unknown. NSCs are generally regarded as non-excitable cells lacking voltage dependent Ca2+ channels. Therefore, the nature of the Ca2+ entry channels that give rise to complex Ca2+ signals in these cells remains unclear. In many non-excitable cells, mobilization of Ca2+ occurs through the opening of Ca2+ release-activated Ca2+ channels (CRAC) encoded by the STIM1/Orai1 proteins. I propose to use CRAC channel subunit, Orai1, knockout studies and in vivo evaluation, such as immunohistochemistry, 2-photon Ca2+ imaging, and migration assays to evaluate their importance in the processes of proliferation, differentiation, and migration in both normal and pathological states of the brain.
|Effective start/end date||7/1/14 → 6/30/16|
- American Heart Association Midwest Affiliate (14PRE20480227)
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