Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging.

HIV 感染、抗逆转录病毒治疗和衰老导致肌肉和骨质流失的新机制。

• 批准号: 10696502
• 负责人: MARK W HAMRICK
• 金额: $ 64.04万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696502
• 关键词: Acceleration; Address; Age; Age Months; Age-Related Bone Loss; Aging; Anabolism; Animal Model; Anti-Retroviral Agents; Aryl Hydrocarbon Receptor; Attenuated; Automobile Driving; Bone Marrow; Bone Marrow Cell Transplantation; Bone Marrow Stem Cell; Bone Resorption; Catabolism; Cell Aging; Data; Development; Diagnosis; Disease Outcome; Disease Progression; Elderly; Enzyme Induction; Fracture; Functional disorder; Funding Opportunities; Future; Gait speed; Genes; Goals; HIV; HIV Infections; HIV-1; HIV/AIDS; Hand Strength; Health; In Vitro; Inflammation; Inflammatory; Intervention; Knock-out; Knowledge; Kynurenine; Longevity; Measures; Methylation; Molecular; Mus; Muscle; Muscle Cells; Muscular Atrophy; Musculoskeletal; Nuclear; Osteogenesis; Osteoporosis; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patients; Phenotype; Play; Public Health; Quality of life; Receptor Activation; Resistance; Role; Signal Pathway; Skeletal Muscle; Skeletal bone; Testing; Thinness; Time; Tissues; Transgenic Mice; Tryptophan; Tryptophan 2,3 Dioxygenase; Wild Type Mouse; aged; antiretroviral therapy; aryl hydrocarbon receptor ligand; bone; bone cell; bone loss; bone mass; bone strength; clinical practice; comorbidity; emtricitabine; experimental study; falls; frailty; functional outcomes; improved; in vivo evaluation; inhibitor; innovation; mechanical properties; mortality; mouse model; multidisciplinary; muscle form; muscle strength; myogenesis; novel; novel therapeutic intervention; overexpression; patient population; pharmacologic; poor health outcome; response; sarcopenia; senescence; stem cells; substantia spongiosa; targeted treatment

Our proposal is in direct response to the special Funding Opportunity Announcement (FOA) PAR-21-068 “Multidisciplinary Studies of HIV/AIDS and Aging (R01)”. A frailty phenotype is frequently observed in HIV patients on long term antiretroviral therapy (ART), and both osteoporosis and sarcopenia are now recognized as co-morbidities among older people with HIV. Loss of muscle mass and strength are in turn associated with poor health outcomes ranging from falls and fractures to accelerated disease progression and increased mortality. Our goal is to address this problem by providing critical, new information on the cellular and molecular mechanisms underlying musculoskeletal dysfunction with HIV infection and ART, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Recent studies identify the aryl hydrocarbon receptor (AhR) as playing a key role in regulating organismal aging and lifespan. Our group has found that AhR activation can induce senescence in bone marrow stem cells, and others have observed that AhR overexpression induces muscle atrophy. Uniting these observations, our central hypothesis is that muscle- and bone-specific AhR activation are key drivers of muscle and bone loss in patients with HIV on ART. Our preliminary data provide a strong rationale for this hypothesis and indicate that 1) markers of muscle atrophy, bone loss, and AhR activation are increased in our mouse model of HIV infection, 2) AhR is highly expressed in muscle and bone, and targeted knockout of AhR in these tissues increases lean mass and trabecular bone mass, 3) pharmacological inhibition of AhR increases muscle strength and markers of bone formation in mice, and 4) the antiretroviral emtricitabine (FTC) increases AhR activation and senescence in muscle cells and these effects are attenuated by AhR silencing. Specific Aim 1 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and HIV infection. Specific Aim 2 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and antiretroviral therapy. Our expected outcomes include 1) defining the role of AhR in skeletal muscle and bone with HIV infection and ART so that it can be targeted therapeutically, and 2) characterizing the impact of aging and ART on AhR activation in skeletal muscle and bone. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of HIV- and age-induced pathologies. Ultimately, these data will enable clinicians to improve disease outcomes and, consequently, public health.

我们的提案是对特别资助机会公告（FOA）PAR-21-068的直接回应 艾滋病毒/艾滋病和老龄化的多学科研究（R 01）。在HIV中经常观察到脆弱表型 长期接受抗逆转录病毒治疗（ART）的患者，骨质疏松症和肌肉减少症现在被认为是 老年艾滋病毒感染者的合并症。肌肉质量和力量的损失反过来又与穷人有关。 健康结果从福尔斯和骨折到加速疾病进展和增加死亡率。 我们的目标是通过提供关键的，新的细胞和分子信息来解决这个问题。 机制与HIV感染和ART的肌肉骨骼功能障碍，从而提高科学的 知识，技术能力，最终临床实践。最近的研究确定了芳烃 受体（AhR）在调节生物体衰老和寿命中起着关键作用。我们小组发现AhR 激活可以诱导骨髓干细胞衰老，其他人已经观察到AhR 过表达诱导肌肉萎缩。结合这些观察，我们的中心假设是，肌肉-和 骨特异性AhR激活是接受ART的HIV患者肌肉和骨丢失的关键驱动因素。 初步数据为该假设提供了强有力的理论基础并表明1）肌肉萎缩的标志物， 在我们的HIV感染小鼠模型中，骨丢失和AhR活化增加，2）AhR在 肌肉和骨骼，靶向敲除这些组织中的AhR增加了瘦体重和骨小梁质量， 3)AhR的药理学抑制增加小鼠的肌肉强度和骨形成的标志物，和4） 抗逆转录病毒恩曲他滨（FTC）增加了肌肉细胞中AhR的激活和衰老， 通过AhR沉默而减弱。具体目标1检验了以下假设：AhR激活是驱动 肌肉和骨质流失与衰老和艾滋病毒感染。具体目标2检验了AhR激活是一种 衰老和抗逆转录病毒治疗导致肌肉和骨质流失的关键因素。我们的预期成果包括：1） 明确AhR在HIV感染和ART的骨骼肌和骨骼中的作用， 2）表征衰老和ART对骨骼肌中AhR活化的影响， 骨头在未来，这些知识可能是诊断，治疗和管理脆弱的关键 患者群体因大量的艾滋病毒和年龄引起的病理而衰弱。最终，这些数据将 使临床医生能够改善疾病结果，从而改善公共卫生。