Musculoskeletal Project 2

肌肉骨骼项目 2

基本信息

批准号：
10231031
负责人：
Mervyn Neale Weitzmann
金额：
$ 38.87万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231031
关键词：
Age Aging Amplifiers Animal Model Anti-Inflammatory Agents Autoimmune Automobile Driving B-Lymphocytes Bone Density Bone Diseases Bone Resorption Bone structure CD4 Positive T Lymphocytes Caring Cells Centers of Research Excellence Chronic Clinical Research Communities Cross-Sectional Studies Cytokine Receptors Defect Deterioration Development Epidemic Estrogens Etiology Event FDA approved Female Fracture Fright Funding Future Gap Junctions Grant HIV HIV Infections HIV antiretroviral Hip Fractures Hip region structure Human Immune Immune system Immunocompromised Host Immunologic Deficiency Syndromes Immunologic Factors Immunologics Incidence Inflammation Inflammatory Lactobacillus casei rhamnosus Ligands Lymphocyte Mediating Menopause Modeling Molecular Musculoskeletal NF-kappa B Osteoclasts Osteogenesis Osteoporosis Ovariectomy PHEMX gene Pharmaceutical Preparations Phase Population Postmenopausal Osteoporosis Postmenopause Prevalence Probiotics Production Rattus Recovery Reporting Research Design Sex Differences Skeletal system Skeleton Source Specialized Center T cell reconstitution T-Lymphocyte TNF gene TRANCE protein Testing Therapeutic Transgenic Organisms Tumor necrosis factor receptor 11b United States National Institutes of Health Viral Woman Women&apos s Interagency HIV Study adaptive immunity antiretroviral therapy bone bone loss bone turnover cytokine fracture risk immune function immune reconstitution inflammatory bone loss inhibitor/antagonist macrophage men mouse model osteoclastogenesis protective effect receptor skeletal success

项目摘要

Project 2-Project Summary HIV-infection causes bone loss that is paradoxically worsened by antiretroviral therapy (ART) leading to significantly increased fracture rates in men and women. However, recent studies show that fracture incidence is further exacerbated in HIV-infected women after the menopause, suggesting a collision between HIV/ART and estrogen deficiency, aggravating skeletal deterioration. While the magnitude of bone loss may vary, all ART drug classes cause bone loss and we have hypothesized that this is an indirect downstream effect of ART, driven by immune-reconstitution and inflammatory events associated with the rekindling of adaptive immunity following T cell reconstitution. We have demonstrated that an animal model of T cell reconstitution does indeed cause significant inflammatory bone loss that closely mimics key features of ART-induced skeletal deterioration. In this model, adaptive immune cells including lymphocytes and macrophages secrete the key osteoclastogenic cytokines Receptor activator of NF-kB ligand (RANKL) and TNF which drives up basal bone resorption leading to bone loss. Interestingly, postmenopausal osteoporosis, the archetypal bone disease of women, results from estrogen decline after menopause that is also driven in part, by an inflammatory state characterized by B and T cell production of RANKL and TNF by adaptive immune cells. Although the etiologies are different, because bone loss in estrogen deficiency and in HIV/ART, both involve activation of adaptive immunity leading to the development of chronic inflammatory states, we hypothesize that a collision between inflammatory bone loss associated with HIV/ART may synergize with the inflammatory bone loss associated with estrogen deficiency. Such events may account for exacerbated fracture in postmenopausal HIV-infected women and may portend a looming epidemic of fracture in the rapidly aging female HIV community. Project 2 of this SCORE grant will study whether HIV/ART- and estrogen deficiency-induced inflammatory events collide to additively or synergistically augment inflammation and bone loss. We will employ animal models of ART- and estrogen deficiency-induced inflammatory bone loss, and translational clinical studies in human HIV+ and HIV- women to quantify the combined effects of HIV/ART and estrogen decline on bone structure and turnover in relation to adaptive immune function and osteoclastogenesis. Our hypotheses, if validated, will significantly inform current understanding of the collision between HIV/ART-induced skeletal decline with that of estrogen deficiency bone loss and the underlying HIV-induced and estrogen deficiency induced immunological defects leading to bone loss and establish whether these defects are additive or synergistic, or even diminished. This will have broad implications for the future of HIV care especially as the population ages.

项目2-项目概要 HIV 感染会导致骨质流失，而抗逆转录病毒治疗 (ART) 反而会加剧骨质流失，从而导致男性和女性的骨折率显着增加。然而，最近的研究表明骨折发生率在绝经后感染艾滋病毒的女性中，这种情况进一步加剧，这表明艾滋病毒/抗逆转录病毒治疗和抗逆转录病毒治疗之间存在冲突。雌激素缺乏，加剧骨骼退化。虽然骨质流失的程度可能有所不同，但所有 ART 药物课程会导致骨质流失，我们假设这是 ART 的间接下游效应，其驱动因素是 T 后与适应性免疫重新点燃相关的免疫重建和炎症事件细胞重建。我们已经证明 T 细胞重建的动物模型确实会导致严重的炎症性骨质流失，与 ART 引起的骨骼退化的关键特征非常相似。在这个模型中，包括淋巴细胞和巨噬细胞在内的适应性免疫细胞分泌关键的破骨细胞细胞因子 NF-kB 配体 (RANKL) 和 TNF 的受体激活剂，可促进基础骨吸收导致骨质流失。有趣的是，绝经后骨质疏松症是女性的典型骨病，其原因是绝经后雌激素下降，部分原因是以 B 和 T 为特征的炎症状态适应性免疫细胞产生 RANKL 和 TNF。虽然病因不同，但由于雌激素缺乏和 HIV/ART 导致的骨质流失，都涉及适应性免疫的激活，导致慢性炎症状态的发展，我们假设炎症性骨质流失之间存在冲突与 HIV/ART 相关的疾病可能与雌激素缺乏相关的炎症性骨质流失产生协同作用。此类事件可能是绝经后感染艾滋病毒的女性骨折加剧的原因，并可能预示着在迅速老龄化的女性艾滋病毒群体中，骨折流行病迫在眉睫。 SCORE 资助的项目 2 将研究 HIV/ART 和雌激素缺乏引起的炎症事件是否相加或协同发生冲突加剧炎症和骨质流失。我们将采用 ART 和雌激素缺乏引起的动物模型炎症性骨质流失，以及针对人类 HIV+ 和 HIV- 女性的转化临床研究，以量化 HIV/ART 和雌激素下降对与适应性免疫相关的骨结构和周转的综合影响功能和破骨细胞生成。我们的假设如果得到验证，将极大地促进目前对 HIV/ART 引起的骨骼衰退与雌激素缺乏性骨质流失之间的冲突潜在的艾滋病毒引起的和雌激素缺乏引起的免疫缺陷导致骨质流失和确定这些缺陷是相加的还是协同的，甚至是减弱的。这将产生广泛的影响对于艾滋病毒护理的未来，特别是随着人口老龄化。