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

基本信息

批准号：
10224669
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
项目类别：
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/10224669
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 Data Store 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

项目摘要

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.