Pathogenesis of HIVAN: the role of Nef
HIVAN 的发病机制:Nef 的作用
基本信息
- 批准号:6895615
- 负责人:
- 金额:$ 12.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-15 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:HIV infectionsSDS polyacrylamide gel electrophoresisbiological signal transductioncell differentiationcell proliferationclinical researchcontact inhibitioncyclinsgenetically modified animalshuman tissueimmunoprecipitationintegrinskidney disorderlaboratory mousemedical complicationmicrofilamentsmicrotubulesnorthern blottingspathologic processprotein protein interactionprotein structure functionsite directed mutagenesistissue /cell culturevirus proteinwestern blottingsyeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant):
HIV-associated nephropathy (HIVAN) is the third leading cause of the end-stage renal disease in African Americans between ages 20-64. One of the pathologic features of HIVAN is collapsing focal segmental glomerulosclerosis (FSGS). Glomerular podocytes, the key cells involved in FSGS, exhibit a disease phenotype characterized by proliferation and dedifferentiation in both human and mouse kidneys with HIVAN. We reported that HIV-1 mRNA were expressed in podocytes of HIVAN patients and of HIV-1 transgenic mice. Studies from transgenic mice suggest that Nef, one of the HIV accessory proteins, plays an important role in the pathogenesis of HIVAN. We found that Nef induces podocyte proliferation and loss of contact inhibition in vitro. In addition, we found that Nef induces podocyte dedifferentiation and the rearrangement of actin filaments. Our preliminary data also suggest that Nef activates Src-Stat3, Ras-MAPK, and Rac1/CDC42 pathways in kidney podocytes. In this study, we propose the following specific aims: 1. To determine in podocytes: a) how Nef induces cell proliferation and loss of contact inhibition by examining the effects of Nef on expressions of cyclins, cyclin inhibitors, integrins, and adhesion molecules; b) how Nef affects the expression of differentiation markers, the organization of actin filaments and microtubules, and the arrangement of actin-associated molecules such as synaptopodin, Ezrin, and CD2AP.
2. To determine in podocytes: a) what are the potential Nef-interactive proteins as well as their down-stream signaling pathways; b) to define the relationships between Nef-induced signaling pathways and Nef-induced phenotypic changes using dominant negative mutants for Src, Stat3, Ras, Rac1/CDC42 or mutants for different Nef binding motifs.
3. To verify that these in vitro findings have in vivo relevance by determining: a) whether Nef induces similar signaling pathways and phenotypic changes in primary cultures of murine podocytes; b) whether these phenotypic changes and signaling pathway activations are observed in kidney podocytes of HIV transgenic mice and HIV patients with HIVAN in vivo. These studies should elucidate essential mechanism responsible for the development of HIV-associated nephropathy and how Nef plays a role in this pathologic process.
描述(由申请人提供):
与HIV相关的肾病(Hivan)是20-64岁非洲裔美国人终末期肾脏疾病的第三主要原因。 Hivan的病理特征之一是折叠局部分段肾小球硬化(FSGS)。肾小球足细胞(与FSG相关的关键细胞)表现出一种疾病表型,其特征是人类和小鼠肾脏中使用Hivan增殖和去分化的特征。我们报道说,HIV-1 mRNA在Hivan患者和HIV-1转基因小鼠的足细胞中表达。来自转基因小鼠的研究表明,NEF是HIV辅助蛋白之一,在Hivan的发病机理中起重要作用。我们发现NEF诱导足细胞增殖和体外接触抑制的丧失。此外,我们发现NEF诱导了肌动蛋白丝的足细胞去分化和重排。我们的初步数据还表明,NEF激活肾脏足细胞中的SRC-STAT3,RAS-MAPK和RAC1/CDC42途径。在这项研究中,我们提出了以下特定目的:1。确定足细胞:a)NEF如何通过检查NEF对细胞周期蛋白,细胞周期蛋白抑制剂,整合素,整合素和粘附分子的表达来诱导细胞增殖和接触抑制作用; b)NEF如何影响分化标记物的表达,肌动蛋白细丝和微管的组织以及与肌动蛋白相关的分子(如突触蛋白突触蛋白,Ezrin和cd2ap)的排列。
2。确定足细胞:a)什么是潜在的NEF相互作用蛋白以及其下游信号通路; b)使用SRC,STAT3,RAS,RAC1/CDC42或用于不同NEF结合基序的SRC,STAT3,RAS,RAC1/CDC42或突变体的主要负突变体使用NEF诱导的信号通路与NEF诱导的表型变化之间的关系。
3。通过确定这些体外发现具有体内相关性:a)NEF是否诱导鼠足细胞原发性培养物的相似信号通路和表型变化; b)在HIV转基因小鼠和HIV患者的HIVAN体内,是否观察到这些表型变化和信号通路激活。这些研究应阐明负责与HIV相关肾病发展的基本机制,以及NEF在这种病理过程中的作用。
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:
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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
Reduction in podocyte 1 SIRT1 accelerates kidney injury in aging mice
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2017 - 期刊:
- 影响因子:0
- 作者:
Peter Y. Chuang;Weijing Cai;Xuezhu Li;Lu Fang;Jin Xu;Rabi Yacoub;John Cijiang He;Kyung Lee - 通讯作者:
Kyung Lee
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
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10678878 - 财政年份:2022
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$ 12.78万 - 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
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10527702 - 财政年份:2022
- 资助金额:
$ 12.78万 - 项目类别:
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10364063 - 财政年份:2021
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Role of RARRES1 in diabetic kidney disease
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10662465 - 财政年份:2021
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Role of RARRES1 in diabetic kidney disease
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10461883 - 财政年份:2021
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$ 12.78万 - 项目类别:
Elucidating the Molecular Mechanisms that Mediate DKD Progression in Patients Living with HIV
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- 批准号:
10531888 - 财政年份:2021
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10399582 - 财政年份:2020
- 资助金额:
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PP2A as a drug target for diabetic kidney disease
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- 批准号:
10627834 - 财政年份:2020
- 资助金额:
$ 12.78万 - 项目类别:
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- 批准号:
10434116 - 财政年份:2020
- 资助金额:
$ 12.78万 - 项目类别:
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