Shared Mechanisms and Markers of Renal Injury and Neurocognitive Impairment in People with HIV

HIV 感染者肾损伤和神经认知障碍的共同机制和标志物

• 批准号: 10013426
• 负责人: ASHA R KALLIANPUR
• 金额: $ 8.05万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013426
• 关键词: APOL1 gene; Acute; Address; African; Aging; Anti-Retroviral Agents; Antioxidants; Biological Markers; Blood Vessels; Brain; Cell physiology; Cerebrospinal Fluid; Chronic; Chronic Kidney Failure; Citric Acid Cycle; Clinical; Cognitive; Cohort Studies; Data; Degenerative Disorder; Development; Disease; Disease Outcome; Early identification; End stage renal failure; Energy Metabolism; Evolution; F2-Isoprostanes; Ferritin; Future; Gait speed; H ferritin; HIV; HIV Infections; HIV Seronegativity; Human; Immune; Immunoglobulins; Impaired cognition; Incidence; Individual; Infection; Inflammation; Inflammation Process; Injury to Kidney; Intervention; Iron; Iron-Binding Proteins; Kidney; Kidney Diseases; L-ferritin; Light; Link; Longitudinal Studies; Manuscripts; Measures; Metabolic; Mitochondria; Motion; Mucins; Neurocognitive; Neurocognitive Deficit; Oligodendroglia; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Plasma; Play; Population; Prospective Studies; Proteins; Quality of life; Regression Analysis; Renal function; Risk; Risk Factors; Role; Serum; Specimen; T-Lymphocyte; Testing; Time; Tissues; Urine; antiretroviral therapy; base; cohort; comorbidity; disorder risk; epidemiology study; experience; ferritin receptor; follow-up; frailty; functional status; high risk; immune function; improved; in vivo; iron metabolism; kidney preservation; link protein; microbial; middle age; mitochondrial dysfunction; mitochondrial metabolism; mortality; novel marker; oxidative damage; prevent; prototype; rat KIM-1 protein; receptor; response; risk variant; theories; urinary; virology

PROJECT SUMMARY People with HIV (PWH) experience an unusually high burden of chronic, aging-related diseases, which have major impact on functional status and quality of life. Chronic kidney disease (CKD) and neurocognitive impairment (NCI) are two prototype disorders of aging that are frequently encountered in this population and may be linked by a common underlying mechanism. While vascular and metabolic factors, in addition to altered mitochondrial metabolism, chronic inflammation and oxidative stress, are implicated in CKD and NCI, the possibility of shared mechanisms that drive development of multiple such disorders in the same individual has not been sufficiently explored. Altered iron metabolism is a fundamental hallmark of aging that links several important aspects of the aging process - inflammation, reduced mitochondrial function, and oxidative stress - and our team has identified levels of a critically important iron-binding protein (ferritin) subunit as an independent predictor of neurocognitive function in a longitudinal study of NCI in PWH on suppressive therapy. Preliminary data link this protein also to CKD in the same individuals. The newly identified receptor in brain for this protein is also expressed in kidney and doubles as a marker of chronic kidney injury (Kim-1), possibly playing a role in CKD. We therefore propose that an HIV-related shift in the ratio of ferritin subunits may explain several aging phenomena in PWH, due to the critical role of one of the subunits in antioxidant responses, immune-cell function, and mitochondrial energy metabolism. In 324 participants from an observational HIV cohort with a wealth of outcome data and biospecimens, we will measure ferritin subunit levels in serum and urinary Kim-1. Specifically, we plan the following: AIM 1: Evaluate associations between ferritin subunit levels, sensitive markers of oxidative stress, and existing plasma metabolite levels in virologically suppressed PWH; AIM 2: Assess associations between urinary Kim-1 and ferritin subunit levels, and evaluate Kim-1 as a noninvasive marker of NCI; AIM 3: Determine associations of ferritin subunits with prevalent and incident CKD, NCI, and frailty outcomes, which are ascertained in this cohort of middle-aged and older PWH, adjusting for important confounders. Results from this proof-of-concept study could significantly improve our understanding of accentuated aging in PWH, highlighting new markers and targets for intervention.

项目摘要 患有艾滋病毒（PWH）的人经历着异常高的慢性，与衰老有关的疾病的负担 对职能状况和生活质量的主要影响。慢性肾脏疾病（CKD）和神经认知 损伤（NCI）是衰老的两个原型疾病，在该人群中经常遇到， 可以通过共同的潜在机制联系在一起。而血管和代谢因素除了改变 线粒体代谢，慢性炎症和氧化应激与CKD和NCI有关， 在同一个人中推动多种此类疾病发展的共同机制的可能性 还没有充分探索。改变铁代谢是衰老的基本标志，它与几个 衰老过程的重要方面 - 炎症，线粒体功能降低和氧化应激 - 我们的团队已经确定了至关重要的铁结合蛋白（铁蛋白）亚基的水平 在抑制性治疗中NCI的纵向研究中，神经认知功能的预测指标。初步的 数据将此蛋白质连接到同一个体中的CKD。该蛋白的大脑中新鉴定的受体是 还用肾脏表达，并以慢性肾脏损伤的标志（KIM-1）双打，可能在 CKD。因此，我们建议与艾滋病毒相关的铁蛋白亚基的比率发生变化可能解释了几个衰老 PWH中的现象，由于其中一个亚基在抗氧化反应中的关键作用，免疫细胞功能， 和线粒体能量代谢。在324位来自观察性艾滋病毒队列的参与者中 结果数据和生物测量，我们将测量血清和泌尿金-1中的铁蛋白亚基水平。具体来说， 我们计划以下内容：AIM 1：评估铁蛋白亚基水平，敏感标志物之间的关联 压力和现有的血浆代谢物水平在病毒学抑制的PWH中；目标2：评估协会 在尿中KIM-1和铁蛋白亚基水平之间，并评估Kim-1是NCI的无创标记。目标3： 确定铁蛋白亚基与普遍和事件CKD，NCI和脆弱的结果的关联，这是 在这一中年和较旧的PWH中确定，调整了重要的混杂因素。结果 概念证明研究可以显着提高我们对PWH中强调衰老的理解，从而强调 干预的新标记和目标。