Musculoskeletal Project 2

肌肉骨骼项目 2

• 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
• 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' 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

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项目摘要 HIV感染会导致骨质流失，抗逆转录病毒疗法（ART）矛盾地恶化 男性和女性的断裂率显着提高。但是，最近的研究表明骨折发生率 更年期后的艾滋病毒感染妇女进一步加剧，这表明艾滋病毒/艺术与 雌激素缺乏，加剧骨骼恶化。虽然骨质流失的大小可能有所不同，但所有艺术药物 课程会导致骨质流失，我们假设这是艺术的间接下游效应，由 与自适应免疫的重新燃烧时，免疫恢复原则和炎症事件 细胞重建。我们已经证明，T细胞重构的动物模型确实确实导致 明显的炎症性骨质流失非常模仿艺术引起的骨骼恶化的关键特征。在这个 模型，包括淋巴细胞和巨噬细胞在内的自适应免疫细胞分泌关键的破骨细胞。 NF-KB配体（RANKL）和TNF的细胞因子受体激活剂，它们驱动基础骨吸收领先 骨丢失。有趣的是，绝经后骨质疏松症，女性的原型骨疾病，由 绝经后的雌激素下降，这也部分由B和T为特征的炎症状态驱动 自适应免疫细胞对RANKL和TNF的细胞产生。尽管病因不同，因为 雌激素缺乏和艾滋病毒/ART中的骨质流失均涉及自适应免疫的激活导致 慢性炎症状态的发展，我们假设炎症性骨质流失之间的碰撞 与HIV/ART相关的可能与与雌激素缺乏相关的炎症性骨质流失协同作用。 这种事件可能会导致绝经后HIV感染的妇女加剧骨折，并可能预期 迅速衰老的女性艾滋病毒群落中骨折的迫在眉睫的流行。该分数的项目2将研究 HIV/ART和雌激素缺乏引起的炎症事件是否相撞或协同性地碰撞 增加炎症和骨质流失。我们将采用艺术和雌激素缺乏诱导的动物模型 炎症性骨质流失以及人类HIV+和HIV妇女的转化临床研究以量化 HIV/ART和雌激素下降对骨骼结构的综合作用与适应性免疫有关 功能和破骨细胞生成。我们的假设，如果得到验证，将大大为当前的理解提供了对 艾滋病毒/艺术引起的骨骼下降与雌激素缺乏骨质流失和 基本的HIV诱导和雌激素缺乏引起的免疫缺陷导致骨质流失和 确定这些缺陷是加性还是协同作用，甚至减少。这将具有广泛的影响 对于艾滋病毒护理的未来，尤其是随着人口年龄的增长。