Immunophilins in the neuroglial response to HIV infection

描述（由申请人提供）：这是我们的发展资助（R21）的修订提交文件，旨在研究HIV感染患者中亲免疫素（IP）和神经变性标志物之间的关联，并测试IP配体（IPL）治疗可能防止由趋化因子介导的HIV相关轴突变性的假设。我们将描述正常和病理分布的FKBP家族的IP尸检脑组织中的HIV感染患者的认知功能障碍和控制。我们还将使用基于人脑细胞培养的体外实验模型来研究IP和突触前装置之间的关联，并分析IPL治疗对HIV感染和胶质细胞活化存在下神经元存活和分化的影响。我们对免疫亲素在HIV感染大脑中慢性神经元损伤反应中所起作用的理解可能会导致识别新的疾病早期标志物。此外，IP可能是治疗干预的理想靶点。目前的研究表明IP配体是有效的神经保护剂，其中一些已经在临床上使用。我们计划研究一个相对较新的丰富的脑蛋白家族的功能，称为免疫亲素（IP），它可能参与HIV感染患者神经元的存活和正常功能。我们对免疫亲素在慢性神经元损伤中所起作用的理解可能会导致神经精神损伤的早期诊断和HIV长期幸存者的潜在治疗干预。目前的研究表明，IP配体具有神经保护作用，其中一些已经在器官移植患者的临床应用中。

DESCRIPTION (provided by applicant): This is a revised submission of our developmental grant (R21) proposing to study the association between immunophilins (IP) and markers of neurodegeneration in HIV infected patients and test the hypothesis that IP ligand (IPL) treatments may protect against HIV-associated axonal degeneration mediated by chemokines. We will characterize the normal and pathologic distribution of the FKBP family of IP in autopsy brain tissues from HIV infected patients with cognitive impairment and controls. We will also use an in vitro experimental model based on human brain cell cultures to study the association between IP and the presynaptic apparatus and analyze the effects of IPL treatments on neuronal survival and differentiation in the presence of HIV infection and glial activation. Our understanding of the role played by immunophilins in response to chronic neuronal injury in the HIV infected brain may lead to identifying new early markers of disease. Furthermore, IP may represent excellent targets for therapeutic interventions. Current studies suggest that IP ligands are potent neuroprotective agents and some of them are already in clinical use. Project Summary We plan to study the function of a relatively new family of abundant brain proteins, called immunophilins (IP), that may be involved in the survival and normal function of neurons in HIV infected patients. Our understanding of the role played by immunophilins in response to chronic neuronal injury may lead to the early diagnosis of neuropsychiatric damage and potential therapeutic interventions in long term survivors with HIV. Current studies suggest that IP ligands are neuroprotective and some of them are already in clinical use in organ transplant patients.