Stem cell therapies could significantly impact our approach for treating diseases, particularly in otherwise incurable neurological disorders. However, to effectively utilize stem cell transplants we must gain a better understanding of both their inherent functions (in providing a renewable source of differentiated cells to damaged areas of the CNS) as well as their interactions with their surrounding environment. Few studies have addressed the potential secondary role for neural stem or progenitor cells in modulating their surroundings, but the implications of this concept could be of importance for stem cell treatments. The overall goal of this proposed study is to investigate mechanisms of communication between neural progenitor cells (NPCs) and other neural cell types. In preliminary studies, I discovered that NPCs can regulate microglia by secreted signaling proteins, and furthermore I identified a specific protein, VEGF, that may mediate this regulation. Therefore, my specific goal is to investigate the hypothesis that NPCs regulate microglia via the secretion of immunomodulatory factors and to explore the molecular mechanisms mediating this regulation by focusing on two Specific Aims: 1) To investigate the direct effects of VEGF protein on microglial functions in vitro, and 2) To study the effects of NPC-derived VEGF on microglial activity and functions in vivo. To address Aim 1, I will analyze several microglia functions with established cell culture assays in which I have treated the microglia with either VEGF protein or conditioned media from NPCs in which I have depleted VEGF with a neutralizing antibody or using a lentiviral shRNA approach. To address Aim 2 I will study microglial phenotypes in two mouse models in which VEGF has been specifically depleted from NPCs. This will again include the use of VEGF-targeted shRNA as well as the inducible Cre-lox system. This is an interdisciplinary project that combines neuroscience and immunology components, and will help to broaden my research skills and knowledge base of both fields. I will gain experience in several techniques including RNA interference and viral techniques as well as Cre-lox technology. Additionally, my training plan includes coursework in both neuroscience and immunology. The conclusions resulting from this project could be of great importance for both basic research and the biomedical field. First, this work offers insight into a novel, immunomodulatory function for NPCs in regulating cells within their microenvironments and aims to elucidate the physiological relevance of this function in endogenous stem cell niches. Furthermore, this could lead to a greater understanding of how transplanted NPCs modulate their surroundings to confer beneficial effects to CNS diseases or injuries, and could ultimately help to improve stem cell therapies.

Public Health Relevance

Medical treatments involving the use of stem cells have shown great potential in treating numerous diseases, particularly neurological disorders that currently have no cure, such as Multiple Sclerosis, Parkinson's disease, and Alzheimer's disease. The goal of this project is to study how stem cells in the brain may communicate with other cells in their immediate environment, and the results of this work could help to improve stem cell therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-N (20))
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Wise, Bradley C
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Stanford University
Schools of Medicine
United States
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Mosher, Kira Irving; Wyss-Coray, Tony (2014) Microglial dysfunction in brain aging and Alzheimer's disease. Biochem Pharmacol 88:594-604
Lucin, Kurt M; O'Brien, Caitlin E; Bieri, Gregor et al. (2013) Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79:873-86