Mechanism of Action of Macrophage Targeted Drugs

巨噬细胞靶向药物的作用机制

• 批准号: 7618640
• 负责人: Kenneth Hadlock
• 金额: $ 24.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618640
• 关键词: Aftercare; Anabolism; Antineoplastic Agents; Blood; Cell Death; Cells; Class; Clinical Trials; DNA; Development; Drug Delivery Systems; FCGR3B gene; Future; Gene Expression; Goals; HIV; Human; Immunosuppressive Agents; In Vitro; Individual; Induction of Apoptosis; Infection; Lead; Macaca mulatta; Macrophage Activation; Messenger RNA; Microarray Analysis; Mononuclear; Numbers; Outcome; Participant; Pathogenesis; Peripheral Blood Mononuclear Cell; Polyamines; Proteins; Recording of previous events; Research Project Grants; Role; SIV; Sampling; Spermine; Therapeutic; Tissues; Treatment Protocols; adenosine deaminase; analog; cellular targeting; design; in vivo; inhibitor/antagonist; insight; killings; macrophage; monocyte; nervous system disorder; novel therapeutics; osteopontin; programs; therapeutic target

HIV infected monocytes and macrophages are involved in the pathogenesis of HIV associated neurological disease (HAND). Pathologica LLC has been systematically investigating compounds that can alter macrophage activation states as potential therapeutics. This class of compounds includes polyamine analogs (e.g. CG47) and enzymatic inhibitors of polyamine synthesis (e.g. PA-001). We have found that polyamine biosynthesis inhibitors (PBIs) are particularly effective at modulating and / or killing CD16 positive macrophages. Preliminary studies at Pathologica have established that the polyamine biosynthesis inhibitor PA01 is very efficient at reducing HIV DNA loads in mononcytes in vitro and at reducing the level of SIV infection of macrophages in the blood and tissues of rhesus macaques. However, the mechanism by which these beneficial outcomes were achieved remains largely unexplored. Microarray analyses of peripheral blood mononuclear cells from HIV infected individuals noted significant changes in the mRNA levels of immomodulatory proteins, including osteopontin and adenosine deaminase after in vitro PBI treatment. These observations are consistent with the recently described immunosuppressive role of the native polyamine spermine in monocytes. Accordingly, we hypothesize that PBIs kill HIV infected CD16+ monocytes and macrophages via an immunomodulatory mechanism involving induction of apoptosis. A more thorough understanding of the mechanism of action of PBIs against HIV infected macrophages will be critical to designing the most efficacious therapeutic regimens for the treatment of HAND. Accordingly, the overall goal of Research Project 1 of this program project is to understand the mechanism by which PBIs lead to reduced HIV proviral load in macrophages in vitro. Mechanistic studies will be performed on monocytes from HIV infected individuals and SIV infected rhesus macaques. Samples provided after treatment of rhesus macaques (Project 2) and clinical trial participants (project 3) with PBIs will allow us to confirm that the mechanism of action of PBIs seen in vitro also is relevant in vivo. These studies should provide significant insight into the role of macrophages in the pathogenesis of HAND and identify novel therapeutic targets for future studies.

HIV感染的单核细胞和巨噬细胞参与HIV相关神经系统疾病的发病机制 疾病（手）。Pathologica LLC一直在系统地研究可以改变 巨噬细胞激活状态作为潜在的治疗方法。这类化合物包括聚胺 类似物（例如CG 47）和多胺合成的酶抑制剂（例如PA-001）。我们发现 多胺生物合成抑制剂（PBIs）在调节和/或杀死CD 16阳性 巨噬细胞Pathologica的初步研究已经确定多胺生物合成抑制剂 PA 01在体外降低单核细胞中的HIV DNA载量和降低SIV水平方面非常有效 恒河猴血液和组织中巨噬细胞的感染。然而， 取得的这些有益成果在很大程度上仍未得到探索。外周血淋巴细胞的微阵列分析 来自HIV感染者的血液单核细胞注意到， 免疫调节蛋白，包括骨桥蛋白和腺苷脱氨酶。 这些观察结果与最近描述的天然免疫抑制剂的免疫抑制作用一致。 单核细胞中的多胺精胺。因此，我们假设PBIs杀死HIV感染的CD 16 + 单核细胞和巨噬细胞通过涉及诱导凋亡的免疫调节机制。一 更深入地了解PBIs对HIV感染的巨噬细胞的作用机制， 这对于设计治疗HAND的最有效治疗方案至关重要。因此 本计划项目研究项目1的总体目标是了解PBIs的机制， 导致体外巨噬细胞中HIV前病毒载量降低。将进行机制研究 来自HIV感染个体和SIV感染恒河猴的单核细胞。之后提供的样品 用PBI治疗恒河猴（项目2）和临床试验参与者（项目3）将使我们能够 证实了体外观察到的PBI的作用机制在体内也是相关的。这些研究应 为巨噬细胞在HAND发病机制中的作用提供了重要的见解， 未来研究的治疗目标。