Elucidating the Molecular Mechanisms that Mediate DKD Progression in Patients Living with HIV

阐明介导 HIV 感染者 DKD 进展的分子机制

• 批准号: 10364063
• 负责人: John Cijiang He
• 金额: $ 85.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364063
• 关键词: Aging; Animal Model; Archives; Automobile Driving; Biopsy; Cells; Chronic; Chronic Kidney Failure; Clinical Data; Collaborations; Complement; Data; Data Set; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease Progression; Dose; Doxycycline; End stage renal failure; Epithelial Cells; Exposure to; Formalin; Gene Expression; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; HIV Seropositivity; HIV therapy; HIV-1; Hepatitis C virus; Human; Hypertension; Immune; In Situ Hybridization; Inflammation; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Leukocytes; Longitudinal Studies; Mediating; Modeling; Molecular; Mus; Online Systems; Organ; PTPRC gene; Paraffin Embedding; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Prevalence; Process; Publishing; RNA; Regimen; Reporting; Sample Size; Scientist; Slide; Streptozocin; System; T-Lymphocyte; Tissues; Transgenic Mice; Transgenic Organisms; Tubular formation; United States; Veterans; Viral Load result; Viremia; age related; antiretroviral therapy; base; cohort; comorbidity; diabetic; diabetic patient; efficacy validation; genetic signature; kidney biopsy; kidney cell; mouse model; new therapeutic target; non-diabetic; novel therapeutics; personalized medicine; podocyte; response; single-cell RNA sequencing; small molecule; targeted treatment; transcriptomics; web portal

SUMMARY With the aging of the HIV-infected population, and their prolonged exposure to cART regimens that may promote the development of diabetes, the prevalence of diabetic kidney disease (DKD) is increasing in patients living with HIV (PLWH). In two recent studies, we and others have confirmed the additive/synergistic effects of HIV infection and diabetes on the progression of DKD. Studies have demonstrated that HIV can infect kidney cells, and that the kidney serves as a reservoir for HIV replication. Recent findings suggest that HIV is present in the kidney even in cART-treated HIV patients. To determine how chronic HIV infection in patients with low or undetectable viral load aggravates DKD, we generated a doxycycline-inducible kidney cell-specific HIV transgenic mouse the expresses low levels of HIV genes. With this model, we confirmed that low level of HIV gene expression did not cause kidney injury alone. However, aggravated DKD was observed after induction of diabetes, suggesting an additive/synergistic effect of HIV and diabetes on DKD progression (Feng J. Kidney Int. 2021). For this project, we will further investigate the molecular mechanisms by which chronic HIV infection induces the progression of DKD in both mouse models and human patients with HIV to accelerate the discovery of new drug targets and therapeutics to treat these patients. Toward this goal, we propose the following specific aims: Aim 1: Perform comprehensive bulk and single-cell RNA-sequencing of the kidneys and kidney immune cells from the mice with both diabetes and low HIV gene expression as compared to control mice, and mice with HIV or diabetes alone. Aim 2: Perform formalin fixed paraffin embedded slides-based RNA-capture sequencing, scRNA-seq, immunostaining, and in-situ hybridization of kidneys from patients with DKD alone, and from those with both HIV infection and DKD. Aim 3: Integrate these datasets together with publicly available datasets to identify gene expression signatures mediating the additive/synergistic effects of HIV and diabetes on DKD progression. Utilize the Connectivity Mapping approach to identify potential drugs and small molecules which could reverse these gene signatures similarly to the approach described in our recent study (Zhang L. Diabetes 2020). Develop a web-portal to serve and interact with all project data. Aim 4: Validate predicted drugs from aim 3 in the animal model described in the aim 1. Overall, this project will enable us to identify potential new mechanisms, new drug targets, and potential new therapeutics to halt the progression of DKD in PLWH.

摘要 随着艾滋病毒感染人口的老龄化，以及他们长期接触CART方案，可能会促进 随着糖尿病的发展，糖尿病肾病(DKD)的患病率正在增加 艾滋病毒(PLWH)。在最近的两项研究中，我们和其他人证实了艾滋病毒感染的相加/协同效应 和糖尿病在DKD进展中的作用。研究表明，艾滋病毒可以感染肾脏细胞，而且 肾脏是艾滋病毒复制的蓄水池。最近的发现表明，艾滋病毒存在于肾脏中。 即使在接受CART治疗的艾滋病毒患者中也是如此。如何确定慢性HIV感染患者的低或未检测到 病毒载量加重DKD，我们产生了一种多西环素诱导的肾脏细胞特异性HIV转基因小鼠 表达低水平的艾滋病毒基因。在这个模型中，我们证实了低水平的艾滋病毒基因表达不会 仅造成肾脏损伤。然而，在诱导糖尿病后观察到加重的DKD，这表明 艾滋病毒和糖尿病对DKD进展的相加/协同作用(冯J.肾，Int.2021年)。对于这个项目， 我们将进一步研究慢性HIV感染导致慢性前列腺癌进展的分子机制。 DKD在小鼠模型和人类HIV感染者中加速发现新的药物靶点和 治疗这些患者。为此，我们提出了以下具体目标：目标1：履行 小鼠肾脏和肾脏免疫细胞的整体和单细胞RNA测序 与对照组小鼠以及单独感染艾滋病毒或糖尿病的小鼠相比，糖尿病小鼠和低HIV基因表达的小鼠的基因表达都较低。 目的2：进行福尔马林固定石蜡包埋玻片RNA捕获测序，scRNA-seq， 单独DKD患者和两种HIV感染者肾脏的免疫染色和原位杂交 感染和DKD。目标3：将这些数据集与公开可用的数据集集成在一起以识别基因 表达信号介导艾滋病毒和糖尿病在DKD进展中的相加/协同效应。利用 识别可能逆转这些变化的潜在药物和小分子的连接图谱方法 基因签名类似于我们最近的研究(张L.糖尿病2020)中描述的方法。发展成为 提供所有项目数据并与之交互的门户网站。目标4：在动物身上验证来自目标3的预测药物 目标1.总体而言，这个项目将使我们能够确定潜在的新机制、新药 靶点，和潜在的新疗法，以阻止DKD在PLWH的进展。