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的化合物 巨噬细胞激活状态作为潜在的治疗方法。此类化合物包括多胺 类似物（例如 CG47）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 (PBI) 在调节和/或杀死 CD16 阳性方面特别有效 巨噬细胞。 Pathologica 的初步研究表明，多胺生物合成抑制剂 PA01 能够非常有效地减少体外单核细胞中的 HIV DNA 载量以及降低 SIV 水平 恒河猴血液和组织中巨噬细胞的感染。然而，其机制 所取得的这些有益成果在很大程度上仍有待探索。外周血微阵列分析 HIV 感染者的血液单核细胞的 mRNA 水平发生显着变化 体外 PBI 处理后的免疫调节蛋白，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药物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 PBI 杀死 HIV 感染的 CD16+ 单核细胞和巨噬细胞通过涉及诱导细胞凋亡的免疫调节机制。一个 更深入地了解 PBI 对 HIV 感染巨噬细胞的作用机制 对于设计最有效的 HAND 治疗方案至关重要。据此， 该计划项目研究项目 1 的总体目标是了解 PBI 的机制 导致体外巨噬细胞中 HIV 前病毒载量减少。将进行机理研究 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 PBI 的体外作用机制在体内也具有相关性。这些研究应该 提供对巨噬细胞在 HAND 发病机制中的作用的重要见解，并确定新的 未来研究的治疗目标。