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.

我们的建议是对特别融资机会公告(FOA)PAR-21-068的直接回应 “艾滋病毒/艾滋病与老龄化的多学科研究(R01)”。在艾滋病毒中经常观察到脆弱的表型。 接受长期抗逆转录病毒治疗(ART)的患者以及骨质疏松症和骨质疏松症患者现在被认为是 老年艾滋病毒携带者的共病。肌肉质量和力量的丧失反过来又与较差的 从跌倒和骨折到疾病加速发展和死亡率增加等各种健康后果。 我们的目标是通过提供关于细胞和分子的关键的新信息来解决这个问题 与艾滋病毒感染和抗逆转录病毒治疗相关的肌肉骨骼功能障碍的机制，从而提高科学研究水平 知识、技术能力，以及最终的临床实践。最近的研究确定了芳烃 受体(AhR)在调节生物衰老和寿命方面起着关键作用。我们小组发现，AhR 激活可以诱导骨髓干细胞衰老，其他人观察到AhR 过度表达会导致肌肉萎缩。结合这些观察，我们的中心假设是肌肉-和 骨骼特异的AhR激活是接受抗逆转录病毒治疗的HIV患者肌肉和骨骼丢失的关键驱动因素。我们的 初步数据为这一假设提供了强有力的理由，并表明1)肌肉萎缩的标志， 在我们的HIV感染的小鼠模型中，骨丢失和AhR激活增加，2)AhR在 肌肉和骨骼，在这些组织中靶向敲除AhR会增加瘦体重和骨小梁质量， 3)药物抑制AhR可增加小鼠的肌肉力量和骨形成指标，以及4) 抗逆转录病毒恩曲他滨(FTC)促进肌肉细胞AhR激活和衰老及其作用 通过AhR沉默而减弱。特定目标1验证了AhR激活是驱动因素的假设 随着年龄的增长和艾滋病毒感染，肌肉和骨骼会减少。《特定目标2》验证了AhR激活是一种 衰老和抗逆转录病毒治疗导致肌肉和骨骼流失的关键因素。我们的预期结果包括1) 明确AhR在感染HIV的骨骼肌和骨骼中的作用以及ART，使其成为靶向 治疗方面，以及2)表征衰老和ART对骨骼肌AhR激活的影响和 骨头。在未来，这一知识可能在诊断、治疗和管理脆弱的疾病方面起到至关重要的作用 患者群体因大量的艾滋病毒和年龄引起的病理而虚弱。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。