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.

我们的建议是直接回应特别资助机会公告（FOA）PAR-21-068 “艾滋病毒/艾滋病和衰老的多学科研究（R01）”。在艾滋病毒中经常观察到脆弱的表型 现在，长期抗逆转录病毒疗法（ART）以及骨质疏松症和肌肉减少症患者被认为是 艾滋病毒老年人的合并症。肌肉质量和力量的损失反过 从跌倒和骨折到加速疾病进展和死亡率增加的健康结果。 我们的目标是通过提供有关细胞和分子的关键信息来解决此问题 肌肉骨骼功能障碍带有艾滋病毒感染和艺术的机制，从而改善了科学 知识，技术能力以及最终的临床实践。最近的研究确定了芳基烃 接收器（AHR）在控制有机衰老和寿命中发挥关键作用。我们的小组发现AHR 激活可以诱导骨髓干细胞中的感应，而其他人则观察到AHR 过表达诱导肌肉萎缩。结合这些观察结果，我们的中心假设是肌肉和 骨特异性AHR激活是ART艾滋病毒患者的肌肉和骨质流失的关键驱动因素。我们的 初步数据为这一假设提供了有力的理由，并表明1）肌肉萎缩的标记，， 在我们的HIV感染的小鼠模型中，骨质流失和AHR激活增加了，2）AHR高度表达 肌肉和骨骼，以及在这些时机中靶向敲除AHR的敲除可以增加瘦小的质量和小梁骨骼， 3）AHR的药理抑制会增加小鼠的肌肉力量和骨骼形成的标记，4） 抗逆转录病毒Emtricerabine（FTC）增加了肌肉细胞中的AHR激活和感应性，这些作用 被AHR沉默减弱。特定的目标1检验了AHR激活是驱动的关键因素的假设 肌肉和骨质流失，衰老和艾滋病毒感染。特定目标2检验了AHR激活是一个假设 通过衰老和抗逆转录病毒疗法驱动肌肉和骨质流失的关键因素。我们的预期结果包括1） 定义AHR在骨骼肌和骨骼中的作用，并具有HIV感染和艺术，以便可以针对目标 在治疗上，以及2）表征衰老和艺术对骨骼肌中AHR激活的影响 骨。将来，这种知识在易受伤害的诊断，治疗和管理中可能至关重要 患者人群因大量的HIV和年龄诱导的病理而衰弱。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。