Effect of Chronic HIV Infection on Progression of Kidney Disease (MSSM)

慢性 HIV 感染对肾脏疾病 (MSSM) 进展的影响

• 批准号: 10155095
• 负责人: John Cijiang He
• 金额: $ 41.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155095
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Acetylation; Acute; Affect; Aging; Agonist; Animal Model; Anti-Retroviral Agents; Attenuated; Bioinformatics; Bromodomain; Cell physiology; Chronic; Chronic Kidney Failure; Clinical; Cohort Studies; Collaborations; Consequences of HIV; Data; Deacetylase; Deacetylation; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease Progression; End stage renal failure; Event; Funding; Gene Chips; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; HDAC1 gene; HIV; HIV Infections; HIV Seropositivity; HIV-1; Hepatitis C virus; Histology; Histone Acetylation; Hypertension; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Mediating; Mitochondria; Molecular; Mus; Pathway interactions; Patients; Prevalence; Proteinuria; Regulation; Reporting; Risk; Role; SIRT1 gene; STAT3 gene; Study models; TP53 gene; Testing; Transcriptional Regulation; Transgenic Mice; Up-Regulation; Veterans; Viral Genes; Viral Load result; age related; antiretroviral therapy; cell injury; comorbidity; diabetic; diabetic patient; effective therapy; epidemiological model; gut microbiome; improved; in vivo; in vivo Model; inhibitor/antagonist; kidney cell; mitochondrial dysfunction; mouse model; novel; overexpression; reactivation from latency; senescence; small molecule; therapeutically effective; transcription factor

PROJECT SUMMARY: With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy (HIVAN) has dramatically decreased in the recent years. Yet, the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV sero-positive patients remains high, suggesting that HIV-positive patients are at increased risk for a variety of acute and chronic kidney diseases. Indeed, several lines of evidence from recent epidemiological and animal model studies indicate that concurrent HIV infection and age-related comorbidities, such as diabetes mellitus, have a synergistic effect on the incidence of chronic kidney disease, thereby necessitating an examination of mechanisms by which HIV infection accelerates the progression of CKD such as diabetic kidney disease (DKD). We have recently shown that the upregulation of local inflammation induced by HIV aggravates the progression of DKD through increased transcriptional activities of NF- κB and STAT3, indicating that HIV-induced chronic inflammation may predispose and excerbate the course of non-HIV related CKD. We have also shown that SIRT1 histone deacetylase is a key modulator of the transcriptional activities of NF-κB and STAT3 in diabetic kidneys, suggesting that pro-inflammatory responses that drive CKD progression may share a common pathway. We therefore posit that SIRT1 is a central modulator of chronic HIV infection-induced inflammation through deacetylation of key transcription factors such as NF-κB and STAT3, and that the regulation of SIRT1 and NF-κB may be effective therapeutic approaches against HIV-induced CKD. Using small molecule agonist of SIRT1 and antagonist of NF-κB, and novel transgenic mouse models, we propose to determine the role of SIRT1 in regulating HIV-mediated cellular injuries in diabetic kidneys. Our results will provide a better understanding of the underlying molecular mechanisms by which chronic HIV infection accelerates the progression of CKD and a proof-of-concept for novel target treatment for CKD in HIV patients.

项目概要： 随着联合抗逆转录病毒药物的广泛使用，艾滋病毒相关的发病率 近年来，慢性肾病（HIVAN）的患病率急剧下降。 HIV 血清阳性患者的肾脏疾病（CKD）和终末期肾脏疾病（ESRD）仍然存在 高，表明艾滋病毒阳性患者患各种急性和慢性疾病的风险增加 事实上，最近的流行病学和动物模型提供了一些证据。 研究表明，并发艾滋病毒感染和与年龄相关的合并症，例如糖尿病 对慢性肾脏病的发病率有协同作用，因此有必要 检查 HIV 感染加速 CKD 进展的机制，例如 我们最近发现局部炎症的上调。 HIV 诱导的 NF-转录活性增加，从而加剧 DKD 的进展 κB 和 STAT3，表明 HIV 诱导的慢性炎症可能诱发并加剧 我们还表明 SIRT1 组蛋白脱乙酰酶是非 HIV 相关 CKD 的关键。 糖尿病肾脏中 NF-κB 和 STAT3 转录活性的调节剂，表明 驱动 CKD 进展的促炎症反应可能具有共同的途径。 因此推测 SIRT1 是慢性 HIV 感染引起的炎症的中央调节剂 通过关键转录因子（如 NF-κB 和 STAT3）的去乙酰化，并且调节 SIRT1 和 NF-κB 可能是对抗 HIV 诱导的 CKD 的有效治疗方法。 SIRT1的分子激动剂和NF-κB的拮抗剂，以及新型转基因小鼠模型，我们 提议确定 SIRT1 在调节糖尿病患者 HIV 介导的细胞损伤中的作用 我们的结果将有助于更好地理解潜在的分子机制。 慢性 HIV 感染会加速 CKD 的进展，这也是新型药物的概念验证 HIV 患者 CKD 的靶向治疗。