Macrophage-Muscle Precursor Cell Interaction in the Context of HIV Infection

HIV 感染背景下巨噬细胞-肌肉前体细胞的相互作用

• 批准号: 7490013
• 负责人: MONTY A MONTANO
• 金额: $ 35.99万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490013
• 关键词: Adult; Adverse effects; Affect; Agonist; Androgen Receptor; Androgens; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Atrophic; Attenuated; Binding; Biochemistry; Biological Markers; Biological Models; Biology; Biopsy; Body Weight decreased; Cell Communication; Cells; Chemotactic Factors; Chromatin; Chromatin Structure; Clinical; Complement Factor B; Condition; Conditioned Culture Media; Endocrinology; Equilibrium; Gene Expression; Genes; Genetic Programming; Genomics; Goals; Growth; Growth Factor; HIV; HIV-1; Human; Immune; In Vitro; Inflammatory; Insulin; MFC; Maintenance; Mediating; Mediator of activation protein; Molecular Virology; Muscle; Muscle Cells; Myoblasts; Myogenic Regulatory Factors; Natural regeneration; Nature; Output; Pathology; Pathway interactions; Patients; Phenotype; Placebos; Process; Proteomics; Recruitment Activity; Research Personnel; Role; Sampling Studies; Signal Pathway; Signal Transduction; Skeletal Muscle; Specimen; Stimulus; Supplementation; Therapeutic; Time; Virus Diseases; Weight Gain; Woman; antiretroviral therapy; base; cell growth; clinically significant; cytokine; design; experience; interest; macrophage; men; monocyte; multidisciplinary; muscle regeneration; myogenesis; precursor cell; programs; repaired; response; satellite cell; success; wasting

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) associated weight loss and muscle wasting remain significant clinical concerns even in the era of potent antiretroviral therapy. The pathogenic sequelae leading to HIV-associated muscle wasting are multi-factorial but can often be characterized by inflammatory muscle degeneration. While androgen supplementation increases muscle mass in treated subjects, significant side effects limit their long-term use. Therefore, there is a need to identify additional mechanisms that promote muscle regeneration. Muscle tissue contains resident muscle precursor cells (MFCs) that are critical in the myogenic regeneration capacity of muscle tissue in response to disuse, damage or atrophy. Notably, in addition to displaying responsiveness to growth promoting androgens, MFCs also release monocyte chemoattractants and require the presence of recruited monocytes / macrophages to repair damaged muscle in animal models. Paradoxically, stimulated macrophages can be pro-inflammatory, raising the possibility for a phenotype that contributes to muscle wasting, rather than promoting muscle growth. HIV infection may tip this balance. The overall objective of this proposal is to characterize the interplay between distinct modes of macrophage stimulation with MFC commitment and differentiation to better understand the conditions that facilitate myogenesis. We hypothesize that HIV infection may favor the emergence of a "classical" pro-inflammatory phenotype, rather than an "alternative" anti-inflammatory phenotype, thereby exacerbating muscle loss. We propose to evaluate the role of macrophage soluble mediators and HIV infection in myogenesis at the immunohistochemical (Aim 1), genomic / proteomic (Aim 2) and chromatin biochemistry (Aim 3) levels to precisely define the muscle genetic program and to distinguish muscle lineage commitment with atrophy signaling. To insure the success of this proposal, we have assembled a multidisciplinary team with expertise in endocrinology, muscle biology, molecular virology and genomics to study macrophage-muscle precursor cell interaction in the context of HIV infection.

描述（由申请人提供）：即使在有效的抗逆转录病毒治疗时代，人类免疫缺陷病毒（HIV）相关的体重减轻和肌肉萎缩仍然是重要的临床问题。导致HIV相关肌肉萎缩的致病性后遗症是多因素的，但通常以炎性肌肉变性为特征。虽然雄激素补充剂增加了治疗受试者的肌肉质量，但显著的副作用限制了其长期使用。因此，有必要确定促进肌肉再生的其他机制。肌肉组织含有常驻的肌肉前体细胞（MFC），其在肌肉组织响应废用、损伤或萎缩的肌源性再生能力中至关重要。值得注意的是，除了显示对促生长雄激素的响应性之外，MFC还释放单核细胞化学引诱物并且需要募集的单核细胞/巨噬细胞的存在来修复动物模型中受损的肌肉。特别是，刺激的巨噬细胞可以是促炎性的，增加了导致肌肉萎缩而不是促进肌肉生长的表型的可能性。艾滋病毒感染可能会打破这种平衡。该提案的总体目标是表征巨噬细胞刺激与MFC定型和分化的不同模式之间的相互作用，以更好地理解促进肌生成的条件。我们假设HIV感染可能有利于“经典”促炎表型的出现，而不是“替代”抗炎表型，从而加剧肌肉损失。我们建议在免疫组化（Aim 1），基因组/蛋白质组学（Aim 2）和染色质生物化学（Aim 3）水平上评估巨噬细胞可溶性介质和HIV感染在肌发生中的作用，以精确定义肌肉遗传程序并区分肌肉谱系承诺与萎缩信号。为了确保这一建议的成功，我们组建了一个多学科团队，拥有内分泌学，肌肉生物学，分子病毒学和基因组学的专业知识，以研究艾滋病毒感染背景下的巨噬细胞-肌肉前体细胞相互作用。