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

项目摘要 艾滋病毒感染者（PWH）经历着异常高的慢性衰老相关疾病负担， 对功能状态和生活质量有重大影响。慢性肾病（CKD）与神经认知 损伤（NCI）是两种在这一人群中经常遇到的衰老的原型障碍， 可以通过一个共同的基本机制联系起来。虽然血管和代谢因素，除了改变 线粒体代谢、慢性炎症和氧化应激与CKD和NCI有关， 在同一个人中驱动多种此类疾病发展的共享机制的可能性， 没有得到充分的探索。铁代谢的改变是衰老的一个基本标志， 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一个至关重要的铁结合蛋白（铁蛋白）亚基的水平，作为一个独立的 在PWH患者接受抑制治疗的NCI纵向研究中，神经认知功能的预测因子。初步 数据将这种蛋白质与同一个体的CKD联系起来。这种蛋白质在大脑中的新受体是 也在肾脏中表达，并作为慢性肾损伤的标志物（Kim-1）加倍，可能在 CKD。因此，我们提出，HIV相关的铁蛋白亚基比例的变化可以解释几种衰老。 PWH中的现象，由于其中一个亚基在抗氧化反应，免疫细胞功能， 和线粒体能量代谢。在来自观察性HIV队列的324名参与者中， 结果数据和生物样本，我们将测量血清和尿Kim-1中的铁蛋白亚基水平。具体地说， 我们计划如下：目的1：评估铁蛋白亚基水平、氧化应激的敏感标志物 病毒学抑制PWH患者的应激和现有血浆代谢物水平; AIM 2：评估相关性 尿Kim-1和铁蛋白亚基水平之间的关系，并评估Kim-1作为NCI的非侵入性标志物; AIM 3： 确定铁蛋白亚基与CKD、NCI和虚弱结局的相关性， 在这个中年和老年PWH队列中确定，调整重要的混杂因素。结果从这个 一项概念验证研究可以显著提高我们对PWH中加速老化的理解， 新的干预指标和目标。

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.