The role of Vpr-mediated cell cycle dysregulation in HIV-associated kidney disease

Vpr 介导的细胞周期失调在 HIV 相关肾病中的作用

• 批准号: 10527702
• 负责人: John Cijiang He
• 金额: $ 77.92万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10527702
• 关键词: AIDS-Associated Nephropathy; Address; Animal Model; Anti-Retroviral Agents; Antimitotic Agents; Apoptosis; Apoptotic; Atrophic; Attenuated; Biopsy Specimen; Bypass; CDC2 gene; CDT1 Gene; Cell Cycle; Cell Cycle Arrest; Cell Cycle Deregulation; Cell Death; Cells; Cessation of life; Chromatin; Chronic; Chronic Kidney Failure; Clinical; Complement; Cytokinesis; DNA Replication Factor; DNA biosynthesis; Defect; Development; Diabetes Mellitus; Diagnosis; Disease Progression; End stage renal failure; Epithelial Cells; Equilibrium; Fibrosis; G2/M Arrest; Gene Expression; Genes; HIV; HIV Infections; HIV therapy; HIV-1; Human; Hyperplasia; Hypertrophy; In Situ; In Vitro; Incidence; Individual; Inflammation; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Knowledge; Licensing; Licensing Factor; Measures; Mediating; Mitosis; Mitotic; Mitotic Cell Cycle; Modeling; Molecular; Monitor; Mus; PLK1 gene; Pathogenesis; Pathologic; Patients; Pharmacology; Phenotype; Phosphotransferases; Polyploid Cells; Polyploidy; Prevalence; Proteins; Proteinuria; RNA; Reporter; Reporting; Risk; Role; Study models; TP53 gene; Therapeutic Effect; Therapeutic Intervention; Time; Transgenic Mice; Tubular formation; Viral Load result; Viral Proteins; age related; antiretroviral therapy; base; cancer cell; cell injury; comorbidity; comparative; effective therapy; epidemiological model; in vivo; inhibitor; interstitial; kidney biopsy; kidney fibrosis; mouse model; new therapeutic target; novel; premature; single-cell RNA sequencing; transcriptomics; vpr Gene Products

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 kidney disease in patients living with HIV remains high, suggesting that HIV predisposes patients to increased risk for chronic kidney disease. 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 even at low viral load accelerates the progression of CKD. Among the HIV-1 viral proteins, we previously showed that HIV viral protein R (Vpr) can induce cell cycle dysregulation, apoptosis, and polyploidy in renal tubular cells. However, the importance and consequences of Vpr-mediated cell cycle arrest and polyploidy has not been fully explored in the setting of kidney disease. In this proposal, we will further dissect the mechanisms dictating the cell fates of Vpr- expressing renal tubular using in vitro approaches (Aim 1). Similarly, using transgenic mice expressing Vpr in renal tubular epithelial cells, we will characterize the cell cycle dysregulation and gene expression at single-cell levels, and determine whether the pharmacological intervention of cell cycle dysregulation can attenuate kidney disease progression in this model, as well as in HIVAN mouse model, Tg26 (Aim 2). To complement the findings in Aims 1 and 2, we will assess the expression of genes and cell cycle regulators in kidney biopsy samples of HIV+ CKD patients (Aim 3). We will also perform transcriptomic profiling for comparative analyses with findings in murine 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.

项目摘要 随着联合抗逆转录病毒药物的广泛使用，HIV相关肾病的发病率 近年来，艾滋病毒/艾滋病的发病率急剧下降。然而，慢性肾病（CKD）的患病率 艾滋病病毒感染者中终末期肾病的发生率仍然很高，这表明艾滋病病毒易于 慢性肾脏疾病的风险增加。事实上，最近的一些证据表明， 流行病学和动物模型研究表明，艾滋病毒感染和年龄相关的合并症， 例如糖尿病，对慢性肾病的发病率具有协同作用， 这就需要研究HIV感染的机制，即使在低病毒载量下， CKD的进展。在HIV-1病毒蛋白中，我们先前表明HIV病毒蛋白R（Vpr）可以 在肾小管细胞中诱导细胞周期失调、凋亡和多倍性。然而，重要性和 Vpr介导的细胞周期停滞和多倍性的后果尚未在以下背景下充分探讨： 肾病在这个提议中，我们将进一步剖析决定Vpr细胞命运的机制， 使用体外方法表达肾小管（目的1）。类似地，使用表达Vpr的转基因小鼠， 肾小管上皮细胞，我们将表征细胞周期失调和基因表达在单细胞 水平，并确定细胞周期失调的药物干预是否可以减弱 肾脏疾病进展在该模型中，以及在HIVAN小鼠模型中，Tg 26（目的2）。以补充 根据目的1和2中的发现，我们将评估肾活检中基因和细胞周期调节因子的表达， HIV+ CKD患者的样本（目标3）。我们还将进行转录组学分析， 在小鼠肾脏中的发现。我们的研究结果将提供一个更好的了解潜在的分子 慢性HIV感染加速CKD进展的机制， HIV患者CKD的新靶向治疗。