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
基本信息
- 批准号:10531888
- 负责人:
- 金额:$ 84.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AccelerationAgingAnimal ModelArchivesAutomobile DrivingBiopsyCellsChronicChronic Kidney FailureClinical DataCollaborationsComplementDataData SetDevelopmentDiabetes MellitusDiabetic NephropathyDiabetic mouseDisease ProgressionDoseDoxycyclineEnd stage renal failureEpithelial CellsExposure toFormalinGene ExpressionGene Expression ProfileGenesGoalsHIVHIV InfectionsHIV SeropositivityHIV therapyHIV-1Hepatitis C virusHumanHypertensionImmuneIn Situ HybridizationInflammationInjuryInjury to KidneyKidneyKidney DiseasesKidney TransplantationKnowledgeLeukocytesLongitudinal StudiesMapsMediatingModelingMolecularMusOrganPTPRC geneParaffin EmbeddingPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPlasmaPopulationPrevalenceProcessPublishingRNARegimenReportingSample SizeScientistSlideStreptozocinSystemT-LymphocyteTherapeuticTissuesTransgenic MiceTransgenic OrganismsTubular formationUnited StatesVeteransViral Load resultViremiaage relatedantiretroviral therapycohortcomorbiditycomparison controldata integrationdiabeticdiabetic patientefficacy validationgenetic signaturekidney biopsykidney cellmouse modelnew therapeutic targetnon-diabeticnovel therapeuticspersonalized medicinepodocyteresponsesingle-cell RNA sequencingsmall moleculetargeted treatmenttranscriptomic profilingtranscriptomicsweb platformweb portal
项目摘要
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.
总结
随着艾滋病毒感染人群的老龄化,以及他们长期接触cART方案,
随着糖尿病的发展,糖尿病肾病(DKD)的患病率在患有糖尿病的患者中正在增加。
艾滋病毒(艾滋病毒携带者)。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叠加/协同效应
和糖尿病对DKD进展的影响。研究表明,艾滋病毒可以感染肾细胞,
肾脏是HIV复制的储存库。最近的研究结果表明,艾滋病毒存在于肾脏中,
即使是接受cART治疗的HIV患者。确定慢性HIV感染患者如何低或检测不到
病毒载量增加DKD,我们建立了一个多西环素诱导的肾细胞特异性HIV转基因小鼠,
表达低水平的HIV基因。利用这个模型,我们证实了HIV基因的低水平表达并不影响
会导致肾损伤。然而,在诱导糖尿病后观察到DKD加重,这表明
HIV和糖尿病对DKD进展的累加/协同效应(Feng J. Kidney Int. 2021)。对于这个项目,
我们将进一步研究慢性HIV感染诱导慢性炎症进展的分子机制。
在小鼠模型和人类HIV患者中进行DKD,以加速发现新的药物靶点,
治疗这些患者的方法。为了实现这一目标,我们提出了以下具体目标:目标1:
对来自患有以下疾病的小鼠的肾脏和肾脏免疫细胞进行全面的批量和单细胞RNA测序:
与对照小鼠和仅患有HIV或糖尿病的小鼠相比,糖尿病和HIV基因表达低。
目的2:进行基于福尔马林固定石蜡包埋载玻片的RNA捕获测序,scRNA-seq,
免疫染色和原位杂交检测DKD单独患者和HIV双阳性患者的肾脏
感染和DKD。目标3:将这些数据集与公开可用的数据集整合在一起,以识别基因
表达特征介导HIV和糖尿病对DKD进展的累加/协同作用。利用
连接性映射方法,以确定潜在的药物和小分子,可以扭转这些
基因签名类似于我们最近的研究中描述的方法(Zhang L.糖尿病2020)。开发一个
门户网站,提供所有项目数据并与之交互。目的4:在动物中验证目的3中预测的药物
目标1中描述的模型。总的来说,这个项目将使我们能够识别潜在的新机制,新的药物,
靶点和潜在的新疗法来阻止PLWH中DKD的进展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John Cijiang He其他文献
Bisphenol A promotes hyperuricemia via activating xanthine oxidase
双酚A通过激活黄嘌呤氧化酶促进高尿酸血症
- DOI:
10.1096/fj.201700755r - 发表时间:
2017-10 - 期刊:
- 影响因子:0
- 作者:
Linqiang Ma;Jinbo Hu;Jiayu Li;Yi Yang;Linkun Zhang;Lingyun Zou;Rufei Gao;Yue Wang;Ting Luo;Xiaojiao Xiang;Hua Qing;Xiaoqiu Xiao;Chaodong Wu;Zhihong Wang;John Cijiang He;Qifu Li;Shumin Yang - 通讯作者:
Shumin Yang
An update: the role of Nephrin inside and outside the kidney
- DOI:
10.1007/s11427-015-4844-1 - 发表时间:
2015-04-29 - 期刊:
- 影响因子:9.500
- 作者:
XueZhu Li;John Cijiang He - 通讯作者:
John Cijiang He
A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury
新发现的C5a受体1在肾小管中对毒素诱导的急性肾损伤的保护作用
- DOI:
10.1016/j.ajpath.2024.10.003 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:3.600
- 作者:
Samuel Mon-Wei Yu;Emily King;Miguel Fribourg;Susan Hartzell;Liam Tsou;Logan Gee;Vivette D. D'Agati;Joshua M. Thurman;John Cijiang He;Paolo Cravedi - 通讯作者:
Paolo Cravedi
Bisphenol A promotes hyperuricemia via activating xanthine oxidase
- DOI:
doi: 10.1096/fj.201700755R - 发表时间:
- 期刊:
- 影响因子:
- 作者:
Linqiang Ma;Jinbo Hu;Jiayu Li;Yi Yang;Linkun Zhang;Lingyun Zou;Rufei Gao;Chuan Peng;Yue Wang;Ting Luo;Xiaojiao Xiang;Hua Qing;Xiaoqiu Xiao;Chaodong Wu;Zhihong Wang;John Cijiang He;Qifu Li;Shumin Yang - 通讯作者:
Shumin Yang
RETRACTED ARTICLE: LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma
撤回文章:长链非编码 RNA HOTAIR 通过抑制肾细胞癌中的 miR-217 调节 HIF-1α/AXL 信号通路
- DOI:
10.1038/cddis.2017.181 - 发表时间:
2017-05-11 - 期刊:
- 影响因子:9.600
- 作者:
Quan Hong;Ou Li;Wei Zheng;Wen-zhen Xiao;Lu Zhang;Di Wu;Guang-yan Cai;John Cijiang He;Xiang-mei Chen - 通讯作者:
Xiang-mei Chen
John Cijiang He的其他文献
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{{ truncateString('John Cijiang He', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 84.11万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 84.11万 - 项目类别:
Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
- 批准号:
10278234 - 财政年份:2021
- 资助金额:
$ 84.11万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 84.11万 - 项目类别:
Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
- 批准号:
10662465 - 财政年份:2021
- 资助金额:
$ 84.11万 - 项目类别:
Role of RARRES1 in diabetic kidney disease
RARRES1 在糖尿病肾病中的作用
- 批准号:
10461883 - 财政年份:2021
- 资助金额:
$ 84.11万 - 项目类别:
PP2A as a drug target for diabetic kidney disease
PP2A作为糖尿病肾病的药物靶点
- 批准号:
10399582 - 财政年份:2020
- 资助金额:
$ 84.11万 - 项目类别:
PP2A as a drug target for diabetic kidney disease
PP2A作为糖尿病肾病的药物靶点
- 批准号:
10627834 - 财政年份:2020
- 资助金额:
$ 84.11万 - 项目类别:
Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies
增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制
- 批准号:
10434116 - 财政年份:2020
- 资助金额:
$ 84.11万 - 项目类别:
Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies
增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制
- 批准号:
10119964 - 财政年份:2020
- 资助金额:
$ 84.11万 - 项目类别:
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