Chemokine Receptor Function in the Nervous System

描述（由申请人提供）：在我们最初的提案中，我们试图证明趋化因子受体在成人大脑神经祖细胞中的表达，以检查SDF1/CXCR4信号传导对齿状回（DG）成人神经祖细胞的影响，并研究hiv对这一过程的影响。我们成功地实施了这些项目。事实上，这种情况已经发展到这样的程度，以致从我们的工作中自然产生了几个新的具体目标。

DESCRIPTION (provided by applicant): In our original proposal we sought to demonstrate the expression of chemokine receptors by neural progenitor cells in the adult brain, to examine the effect of SDF1/CXCR4 signaling on adult neural progenitor cells in the dentate gyrus (DG), and to investigate the effects of HIV1 on this process. We have successfully pursued these projects. Indeed, this has occurred to such an extent that several new Specific Aims have naturally developed from our work. A significant achievement has been the development of several different lines of two color BAC transgenic mice that report the expression of chemokines (SDF1, MCP1-RED) and their receptors (CXCR4, CCR2-GREEN). These mice allowed us to demonstrate that SDF1 took on a new role and acted as a neurotransmitter within the neural stem cell niche (NSN) of the adult DG. We demonstrated that SDF1 cooperated with GABA in synaptic transmission to CXCR4 expressing neural progenitors in the DG NSN. These observations indicate that both HIV1 (T-tropic) or chronic morphine use may directly influence neurogenesis by impacting this SDF1 utilizing synapse in the DG NSN, a new Aim which we now wish to pursue. We also observed that SDF1 was expressed by endothelial cells that line blood vessels in the DG NSN indicating that SDF1 potentially released from both vascular and neuronal sources may influence neurogenesis. These observations have suggested a new Aim in which we would genetically delete SDF1 from either neuronal or endothelial sources and examine its effects on neurogenesis under normal and pathological conditions. We have created a line of mice with a conditional SDF1 allele and now wish to carry out this additional Aim. The use of our new MCP-1-Red/CC2-Green mice has allowed us to examine the role of the innate immune response in the DG NSN. The innate immune response is activated by HIV1 and recruits cells such as activated microglia and leukocytes to the DG NSN. Using these mice we have observed the activation of the innate immune response by HIV1 and by other types of infection or brain damage. The idea that cells that form part of the innate immune response may also constitute part of the DG NSN under pathological conditions is a new idea suggesting ways in which innate immunity may interact with adult neurogenesis. These observations have suggested a new Aim in which we will examine the overall effect of innate immunity triggered by HIV1 and morphine on neurogenesis in the DG NSN. We believe that chemokine signaling, particularly involving MCP1 acting via the CCR2 receptor will mediate such actions. PUBLIC HEALTH RELEVANCE. We have demonstrated that adult neurogenesis in the dentate gyrus stem cell niche can be influenced by the chemokine SDF1.SDF1 expressing neurons cooperate with GABA in forming synaptic inputs to neural progenitor cells.We now wish to determine how the innate immune response that is triggered by HIV1 can influence the development of neurons in the adult DG and how this can also be modified by chronic morphine treatment.We shall utilize novel lines of chemokine reporter and knockout mice to determine how the cellular elements of the innate immune system can form a functional part of the adult stem cell niche and how neurogenic events can be regulated by chemokines and their receptors under normal conditions and in the context of neuropathology.