Project 2

项目2

• 批准号: 8102895
• 负责人: Steven Daniel Douglas
• 金额: $ 21.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102895
• 关键词: ARRB2; Antidepressive Agents; Antiviral Response; Blinded; Blood specimen; CCR5 gene; Cell Culture Techniques; Cell physiology; Cells; Clinical Trials; Depressed mood; Down-Regulation; Drug Receptors; Fluorescence Microscopy; Funding; Gagging; Goals; HIV; HIV Infections; Hamilton Rating Scale for Depression; In Vitro; Individual; Infection; Investigation; Ligands; Ligation; Measures; Mediating; Mental Depression; Modeling; National Institute of Mental Health; Natural Killer Cells; PTPN11 gene; PTPN6 gene; Pharmaceutical Preparations; Phase; Phosphorylation; Predisposition; RANTES; Relative (related person); Ritonavir; Substance P; Substance P Receptor; TACR1 gene; Viral; Viral Load result; Viral Physiology; Woman; aprepitant; functional improvement; functional restoration; improved; in vivo; macrophage; men; monocyte; peripheral blood; receptor; response

The neurokinin-1 antagonists (SP antagonist) CP96,345 and aprepitant inhibit HIV infectivity of monocytederived macrophages, derived from healthy individuals and studied in ex vivo cell cultures. We have extended these findings to a two-week in vivo setting in a Phase IB clinical trial (IND 75558 Clinical Trial NCT00428519) in HIV-infected subjects with detectable viral loads and CCR5 HIV strains, and we are awaiting the results of this ongoing blinded clinical trial. The proposed study of NKIR antagonists will be performed using peripheral blood samples to be obtained through recruitment with another NIMH funded study (R01-MH082670, 2008-2013, "Depression, Antidepressants and HIV infectivity") in ex vivo cells obtained from depressed and non-depressed HlV-negative men and women. The goal is to determine whether depression alters susceptibility of cells to HIV infectivity ex vivo. In our long-standing investigations, we have observed differences in resopnise to NKIR antagonists (CP96,345 and aprepitant) related to susceptibility of monocyte-derived macrophages (MDMs) from healthy donors to viral challenge. In this project, we will further investigate anti-viral activity of selected NKI R antagonists targeted against cells from HIV-infected individuals and cells investigated ex viVo from individuals with different levels of depression as determined by Hamilton Depression scales and other standard psychiatric measures. We hypothesize that aprepitant inhibits HIV entry and replication in MDMs. We further hypothesize that this effect is mediated through CCR5 down-regulation. We predict that MDMs from subjects with depression will be infected with an HIV ex vivo model more readily and will demonstrate better responses to NKIR antagonists compared with cells from non-depressed subjects. We further propose that Natural Killer cells from subjects with depression will have impaired Natural Killer cell functions relative to impaired ligation of inhibitory Natural Killer cell receptors and that treatment with NK1R antagonists will restore these functions. The ex vivo efficiacy of NKIR antagonists in cells from depressed subjects will be determined.

Neurokinin-1拮抗剂（SP拮抗剂）CP96,345和Aprepitant抑制单核细胞的HIV感染性 巨噬细胞源自健康个体，并在离体细胞培养物中进行了研究。我们有 在IB期临床试验中将这些发现扩展到两周的体内环境（IND 75558临床试验 NCT00428519）在可检测的病毒载荷和CCR5 HIV菌株的HIV感染受试者中，我们是 等待这项正在进行的盲目临床试验的结果。拟议的NKIR拮抗剂研究将是 使用外周血样本通过另一位NIMH资助来获得 研究（R01-MH082670，2008-2013，“抑郁，抗抑郁药和HIV感染性”）在体内细胞中 从沮丧和不抑郁的HLV阴性男性和女性获得。目标是确定 抑郁症是否会改变细胞对HIV感染性的敏感性。在我们的长期调查中 我们已经观察到与NKIR拮抗剂（CP96,345和Aprepitant）的重新解散差异 单核细胞衍生的巨噬细胞（MDM）从健康供体到病毒挑战的敏感性。在这个 项目，我们将进一步研究针对细胞的选定NKI R拮抗剂的抗病毒活性 艾滋病毒感染的个体和细胞从不同程度的抑郁水平的个体中调查的人和细胞为 由汉密尔顿抑郁量表和其他标准精神病措施确定。我们假设这一点 Aprepitant抑制MDMS中的HIV进入和复制。我们进一步假设这种效果是介导的 通过CCR5下调。我们预测，来自抑郁受试者的MDM将被感染 HIV离体模型更容易，并且将表现出对NKIR拮抗剂的更好反应 来自不抑郁的受试者的细胞。我们进一步提出，抑郁受试者的天然杀手细胞 相对于抑制性天然杀伤细胞的连接受损而受损的天然杀伤细胞功能会受损 受体和用NK1R拮抗剂的治疗将恢复这些功能。离体的效力 将确定来自抑郁受试者细胞中的NKIR拮抗剂。