Macrophages Role in the Development of HIV Lipoatrophy

巨噬细胞在 HIV 脂肪萎缩发展中的作用

基本信息

批准号：
7232646
负责人：
DEIRDRE A KILLEBREW
金额：
$ 4.18万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232646
关键词：
Adipocytes Adipose tissue Anterior Anti-Retroviral Agents Biopsy CCL2 gene Cells Chronic DNA Development Diagnosis Etiology Fatty acid glycerol esters Fellowship Flow Cytometry Functional disorder Gene Expression HIV HIV Seropositivity HIV-1 Highly Active Antiretroviral Therapy IL6 gene Immunohistochemistry Individual Infiltration Inflammation Inflammatory Lateral Lipoatrophy Lipodystrophy Literature Localized Metabolic syndrome Mitochondria Mitochondrial DNA Names Nucleosides Numbers Oxidative Phosphorylation Oxidative Stress Participant Patients Pattern Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Polymerase Chain Reaction Population Production Proteins RNA Reverse Transcriptase Inhibitors Role Schedule Small Inducible Cytokine A3 Testing Thigh structure Time cytokine macrophage mitochondrial dysfunction peripheral blood protein expression social stigma subcutaneous wasting

项目摘要

DESCRIPTION (provided by applicant): HIV lipoatrophy, the wasting of subcutaneous adipose tissue, is part of the metabolic syndrome in 50-70% of patients on highly active antiretroviral therapy (HAART). Lipoatrophy leads to social stigma that can inhibit a patient from adhering to the prescribed medication schedule. We have shown that one of the causes of HIV lipoatrophy is mitochondrial dysfunction due to the HIV drugs, nucleoside reverse transcriptase inhibitors (NRTIs). Additionally, the role of inflammation has been suggested in the literature to influence the development of lipoatrophy. An increase in proinflammatory cytokines has been found in HIV positive patients, as well as those diagnosed with lipodystrophy. However, the etiology of the origin of this cytokine production has yet to be elucidated. Our hypothesis is that peripheral blood macrophages (MDMs), activated by HIV-1, infiltrate adipose tissue and produce pro-inflammatory cytokines. This chronic inflammation caused by MDMs amplifies the mitochondrial dysfunction and oxidative stress induced in adipose tissue by antiretroviral medications. We will examine immunological and mitochondrial parameters in MDMs and gluteal fat biopsies cells from Lipoatrophic (HIV+) (n=15), Non-Lipoatrophic (HIV+) (n=15), NTRI naive (HIV+) (n=15), and HIV negative participants (n=15). We will isolate adipocytes and a preadipocytes fraction (with the macrophages) from the fat biopsies and assess for: macrophages by CD68 expression, cytokine expression, mtDNA copies/cell, and RNA and protein expression of mitochondrial oxidative phosphorylation.

描述（由申请人提供）：HIV 脂肪萎缩，即皮下脂肪组织的消耗，是 50-70% 接受高效抗逆转录病毒治疗 (HAART) 的患者代谢综合征的一部分。脂肪萎缩会导致社会耻辱，从而阻碍患者遵守规定的用药时间表。我们已经证明，HIV 脂肪萎缩的原因之一是 HIV 药物核苷逆转录酶抑制剂 (NRTI) 导致的线粒体功能障碍。此外，文献表明炎症的作用会影响脂肪萎缩的发展。在艾滋病毒阳性患者以及被诊断患有脂肪营养不良的患者中发现促炎细胞因子增加。然而，这种细胞因子产生起源的病因学尚未阐明。我们的假设是，HIV-1 激活的外周血巨噬细胞 (MDM) 会渗透脂肪组织并产生促炎细胞因子。这种由 MDM 引起的慢性炎症会加剧抗逆转录病毒药物在脂肪组织中引起的线粒体功能障碍和氧化应激。我们将检查来自脂肪萎缩性 (HIV+) (n=15)、非脂肪萎缩性 (HIV+) (n=15)、NTRI 原始 (HIV+) (n=15) 和 HIV 的 MDM 和臀部脂肪活检细胞的免疫学和线粒体参数负面参与者 (n=15)。我们将从脂肪活检中分离脂肪细胞和前脂肪细胞部分（带有巨噬细胞），并通过 CD68 表达、细胞因子表达、mtDNA 拷贝/细胞以及线粒体氧化磷酸化的 RNA 和蛋白质表达来评估巨噬细胞。