Immunophilins in the neuroglial response to HIV infection

描述(由申请人提供)：这是我们的发展拨款(R21)的修订申请，建议研究免疫亲和素(IP)和HIV感染患者神经变性标志物之间的联系，并测试IP配体(IPL)治疗可能防止由趋化因子介导的HIV相关轴突退化的假设。我们将从HIV感染的认知障碍患者和对照组的尸检脑组织中鉴定FKBP IP家族的正常和病理分布。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与突触前装置的关联，并分析在HIV感染和神经胶质激活存在的情况下，IPL治疗对神经元存活和分化的影响。我们对免疫亲和素在应对HIV感染的大脑中的慢性神经元损伤中所起的作用的理解，可能会导致识别新的疾病早期标志物。此外，IP可能是治疗干预的极佳靶点。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。项目概述我们计划研究一个相对较新的丰富的脑蛋白质家族的功能，称为免疫亲和素(IP)，它可能参与HIV感染患者神经元的生存和正常功能。我们对免疫亲和素在应对慢性神经元损伤中所起作用的理解可能有助于早期诊断HIV长期存活者的神经精神损害和潜在的治疗干预。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上使用。

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.