This project is to determine the molecular basis of how the neuro-vascular interactions lead to their functional interdependence in tissue homeostasis. Given the importance of the vascular niche to support a variety of stem cells, we discovered vascular paracrine signals for neural stem cell (NSC) maintenance. We generated a mouse model for the human disease Cerebral Cavernous Malformation (CCM), that develops CCM disease-like brain hemorrhage and neurologic defects due to conditional deletion of endothelial ccm2, suggesting that the malformed brain vasculature influences the maintenance of functional neuronal network (Hum Mol Genet. 2011). Our genetic ablation of endothelial capillaries in the neurogenic subventricular zone (SVZ) of adult brain demonstrated the importance of the vascular niche in NSC maintenance. We utilize a systematic multi-faceted approach to identify and validate the vascular niche signals involved in maintenance, self-renewal, proliferation and differentiation of neural stem cells (manuscript in revision for publication). We are now evaluating the physiological relevance of the candidate niche signals in vitro and in vivo. Understanding the mechanisms by which vascular niche signals maintain NSCs is an essential prerequisite for the manipulation of NSCs for transplantation therapy of neurological diseases.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$511,457
Indirect Cost
Name
National Heart, Lung, and Blood Institute
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Type
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Arnold, Thomas D; Niaudet, Colin; Pang, Mei-Fong et al. (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain. Development 141:4489-99
Okabe, Keisuke; Kobayashi, Sakiko; Yamada, Toru et al. (2014) Neurons limit angiogenesis by titrating VEGF in retina. Cell 159:584-96
Kim, Kee K; Nam, Joseph; Mukouyama, Yoh-Suke et al. (2013) Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development. J Cell Biol 200:443-58
Lee, Cheol; Hu, Jingqiong; Ralls, Sherry et al. (2012) The molecular profiles of neural stem cell niche in the adult subventricular zone. PLoS One 7:e50501