Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 (NK1-R) Antagonists

使用 Neurokinin-1 (NK1-R) 拮抗剂进行抗 HIV 神经免疫调节治疗

• 批准号: 8303327
• 负责人: Steven Daniel Douglas
• 金额: $ 112.34万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303327
• 关键词: AIDS neuropathy; Address; Affect; Anti-HIV Agents; Antiviral Agents; Astrocytes; Biological Assay; Biometry; Blinded; Blood - brain barrier anatomy; Brain; CCR5 gene; CXCL12 gene; Cells; Chemokine (C-C Motif) Receptor 5; Chemotaxis; Clinical; Clinical Trials; Development; Down-Regulation; Fostering; HIV; HIV Envelope Protein gp120; HIV-1; Human; IMPAACT; Immune; Immune system; Immunologics; Infection; Instruction; Length; Licensing; Ligand Binding; Macaca mulatta; Measures; Mediating; Medicine; Mental Depression; Molecular; Natural Immunity; Natural Killer Cells; Nuclear Pore Complex; Pediatrics; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Philadelphia; Psychiatry; RANTES; Research Personnel; Ritonavir; Role; Safety; Series; Signal Transduction; Stromal Cell-Derived Factor 1; Substance P; Substance P Receptor; Surface; TACR1 gene; Tachykinin; Tail; Testing; Viral; aprepitant; bench to bedside; brain cell; improved; macrophage; medical schools; monocyte; nerve stem cell; neurobehavioral; new therapeutic target; novel; pre-clinical; programs; receptor; response

The neurokinin receptor (NK1R), the substance P-preferring receptor, is a novel therapeutic target for neuroAIDS. Neurokinin-1 receptor antagonists (NK1RA) have antiviral activity, positive immunomodulatory effects and neurobehavioral effects. We have demonstrated significant ex vivo anti-HIV activity in monocyte- derived macrophages of NK1RA, which include the FDA licensed drug, aprepitant. The antiviral effect is mediated, in part, through CCR5 down-regulation. Aprepitant crosses the blood-brain barrier. Aprepitant is safe in rhesus macaques, and we have an ongoing two-week blinded Phase IB clinical safety trial of aprepitant in HIV-infected humans (NCT00428519). In this new program-project application, we propose a novel series of studies which will determine the mechanism of action of NK1R. There are three interactive preclinical and clinical projects, which target the development of NK1RA therapy for neuroAIDS: 1) Cellular Mechanisms-Neurokinin-1 R Antagonists in the Brain and Immune System; 2) Immune Mechanisms-Anti- HIV Actions of Neurokinin-1 R Antagonists in Depression; and 5) Phase IB Clinical Trial of Neurokinin-1 R Antagonist-Aprepitant with ritonavir boost and direct proof of NK1R antagonism efficacy, and two Cores: A) Administration; and C) Quantitative Pharmacology and Biostatistics. The optimization of the use of NKI RA in neuroAIDS therapy is proposed and the program-project encompasses basic, translational, and clinical HIV studies of tachykinin (substance P) and NK1RA. The investigators from the Joseph Stokes, Jr. Rl, CHOP, the UPenn Schools of Medicine (Depts. of Pediatrics, Psychiatry, & Medicine) and Westat. The Philadelphia ACTU and IMPAACT CTU's, Penn-CHOP CFAR, and Penn CTSU foster the proposed interactions. These molecular, immunologic, pharmacologic, and bench-to-bedside projects address this novel therapeutic target for neuroAIDS treatment. RELEVANCE (See Instructions): An integrated pre-clinical/clinical program (IPCP) is proposed to use NK1RA as anti-HIV agents in neuroAIDS. This class of receptor antagonists crosses the blood brain barrier. This NK1RA has activity as an antiviral HIV agent that improves innate immunity (Natural Killer cells) and has positive neurobehavioral effects. NK1RA are a potential novel therapy for neuroAIDS.

神经激素受体（NK1R），物质p优先受体，是一个新型的治疗靶点 神经辅助。 Neurokinin-1受体拮抗剂（NK1RA）具有抗病毒活性，阳性免疫调节性 作用和神经行为效应。我们已经在单核细胞中显示出显着的离体抗HIV活性 NK1RA的衍生巨噬细胞，其中包括FDA许可的药物，Aprepitant。抗病毒作用是 部分通过CCR5下调介导。偶然性跨越血脑屏障。 Aprepitant是 在恒河猕猴中安全，我们进行了一项持续的两周的IB临床安全试验 艾滋病毒感染的人（NCT00428519）。在这个新的程序项目应用程序中，我们提出了一个 新的一系列研究将决定NK1R的作用机理。有三个互动 临床前和临床项目，针对NK1RA神经辅助疗法的发展：1）细胞 机理 - 神经蛋白1 R拮抗剂和免疫系统中的拮抗剂； 2）免疫机制 - 抗 Neurokinin-1 R拮抗剂在抑郁症中的艾滋病毒作用； 5）神经蛋白1 R的IB期IB临床试验 具有利托那韦的拮抗剂 - 宾夕法尼亚，直接证明了NK1R拮抗功效，两个核心：A） 行政; c）定量药理学和生物统计学。优化使用NKI RA 提出了神经辅助治疗，该程序项目包括基本，转化和临床HIV 速素（物质P）和NK1RA的研究。 Joseph Stokes，Jr。RL，Chop，Chop， Upenn医学院（儿科，精神病学和医学系）和Westat。费城 Actu和Incract CTU，Penn-Chop CFAR和Penn CTSU促进了拟议的相互作用。这些 分子，免疫学，药理学和基准对床头项目解决这个新型治疗靶标 用于神经辅助治疗。 相关性（请参阅说明）： 提议综合临床前/临床计划（IPCP）将NK1RA用作抗HIV药物 神经辅助。这类受体拮抗剂越过血脑屏障。这个NK1RA的活动是 改善先天免疫力（天然杀伤细胞）并且具有阳性神经行为的抗病毒药毒剂 效果。 NK1RA是一种潜在的神经助剂的新疗法。