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

描述（由申请人提供）：即使在强效抗逆转录病毒治疗的时代，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，但通常可以以炎症性肌肉变性为特征。虽然雄激素补充剂增加了治疗对象的肌肉质量，但显著的副作用限制了它们的长期使用。因此，有必要确定促进肌肉再生的其他机制。肌肉组织含有常驻肌前体细胞（MFCs），它们在肌肉组织废弃、损伤或萎缩时的肌原性再生能力中起着关键作用。值得注意的是，在动物模型中，除了显示对促生长雄激素的反应外，mfc还释放单核细胞化学引诱剂，并需要募集的单核细胞/巨噬细胞的存在来修复受损的肌肉。矛盾的是，受刺激的巨噬细胞可能是促炎的，增加了导致肌肉萎缩的表型的可能性，而不是促进肌肉生长。HIV感染可能会打破这种平衡。本提案的总体目标是表征巨噬细胞刺激不同模式与MFC承诺和分化之间的相互作用，以更好地了解促进肌肉形成的条件。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。我们建议在免疫组织化学（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感染在肌肉发生中的作用，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的团队，具有内分泌学，肌肉生物学，分子病毒学和基因组学的专业知识，研究HIV感染背景下巨噬细胞-肌肉前体细胞相互作用。

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.