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- Immunology of neural stem cell fate and function
One of the most difficult yet ultimately rewarding goals in stem cell research is to repair damaged neural systems with newly generated neurons. Our work examining neuronal integration and survival in the postnatal and adult brain shows that incoming neurons are uniquely and exquisitely sensitive to the immune response and inflammation that is always present when cells are transplanted into the injured or diseased brain or spinal cord. Here we propose to: 1) further refine our understanding of the molecular mechanisms that promote or inhibit new neuron integration; 2) evaluate pharmacological or biological methods for enhancing transplant efficiency and 3) test the developed techniques in a model of stem cell therapy for treating children who suffer neurological damage due to treatment for brain cancer. Future studies anticipate the use of these interventions to improve stem cell therapies for a variety of neurological injuries and diseases.
The proposed studies focus on a critical yet poorly characterized aspect of stem cell therapy in the brain and spinal cord. Advances in these studies would not only stimulate new clinical studies but would also create novel biotechnologies, bringing new commercial opportunities to the state of California. The emphasis on immunological aspects of cellular transplant in this proposal are not only applicable in a neurological context but may be broadly beneficial across many therapies where stem cell-derived transplants are contemplated.
Publications
- J Neurosci (2013) Neuronal rac1 is required for learning-evoked neurogenesis. (PubMed: 23884931)
- Brain Behav Immun (2013) Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis. (PubMed: 23402793)
- Brain Behav Immun (2012) Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation. (PubMed: 23041279)
- Brain Behav Immun (2012) PPARgamma activation prevents impairments in spatial memory and neurogenesis following transient illness. (PubMed: 23108061)
- Soft Matter (2011) Vacuum soft lithography to direct neuronal polarization
- PLoS One (2011) MHC Mismatch Inhibits Neurogenesis and Neuron Maturation in Stem Cell Allografts. (PubMed: 21479168)
- Mol Cell Neurosci (2010) Characterization of axon guidance cue sensitivity of human embryonic stem cell-derived dopaminergic neurons. (PubMed: 20637284)
- J Neurosci (2010) Mitochondrial protection attenuates inflammation-induced impairment of neurogenesis in vitro and in vivo. (PubMed: 20844120)
- Stem Cells (2009) Endogenous Wnt signaling maintains neural progenitor cell potency. (PubMed: 19418460)
- Mol Cell Neurosci (2009) A central role for the small GTPase Rac1 in hippocampal plasticity and spatial learning and memory. (PubMed: 19394428)
- Neuron (2009) Immune influence on adult neural stem cell regulation and function. (PubMed: 19840551)
- Hum Mol Genet (2008) Cellular repair of CNS disorders: an immunological perspective. (PubMed: 18632702)
- Proc Natl Acad Sci U S A (2008) Wnt-mediated self-renewal of neural stem/progenitor cells. (PubMed: 18957545)