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: 10678878
• 负责人: John Cijiang He
• 金额: $ 74.03万
• 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/10678878
• 关键词: AIDS-Associated Nephropathy; Acceleration; 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; 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; cancer cell; cell injury; comorbidity; comparative; effective therapy; epidemiological model; in vivo; inhibitor; interstitial; kidney biopsy; kidney fibrosis; mouse model; new therapeutic target; novel; pharmacologic; premature; single-cell RNA sequencing; transcriptome sequencing; transcriptomic profiling; 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.

项目总结

项目成果

HIV-1 infection of renal epithelial cells: 30 years of evidence from transgenic animal models, human studies and in vitro experiments.

• DOI: 10.1186/s12977-023-00617-8
• 发表时间: 2023-03-16
• 期刊: Retrovirology
• 影响因子: 3.3