p66ShcA in HIV associated Nephropathy

p66ShcA 在 HIV 相关肾病中的作用

基本信息

批准号：
8440810
负责人：
PRAVIN C SINGHAL
金额：
$ 57.71万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440810
关键词：
AIDS-Associated Nephropathy Acquired Immunodeficiency Syndrome African American Animals Antioxidants Apoptosis Attenuated Cell Nucleus Cells Characteristics Chronic Kidney Failure Clinical Communication DNA Repair Development Disease Disease Progression Double Strand Break Repair Drug Metabolic Detoxication End stage renal failure Focal Segmental Glomerulosclerosis Gene Expression Generations Genes Genetically Engineered Mouse Genome Goals HIV HIV-1 Hospitalization Human In Vitro Incidence Individual Infection Kidney Kidney Diseases Lesion Mediating Mitochondria Mus Mutation Outcome Study Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Population Prevention Production Proteins Reactive Oxygen Species Renal glomerular disease Research Resistance Role Sirolimus Stress Testing Therapeutic Tubular formation attenuation base glomerulosclerosis human FRAP1 protein mTOR Inhibitor men mouse model mutant novel therapeutics podocyte prevent programs public health relevance senescence therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by focal segmental glomerular sclerosis (FSGS) and tubulointerstitial lesions. Preliminary studies by others and us have indicated that many of the effects of HIV-1 infection are mediated via oxidative stress which results from the generation of reactive oxygen species (ROS). Recently, pivotal role of p66ShcA proteins have been identified in the generation of oxidative stress. The long term objective of the present proposal is to develop novel therapeutic strategies, targeting mutant genes or dysfunctional gene products, to arrest or prevent the development of HIVAN. Our recent preliminary studies in Tg26 (a mouse model of HIVAN) animals have shown that both glomerular and tubular cells showed enhanced generation of ROS. In addition, in in vitro studies, podocytes-transduced with HIV-1 not only showed enhanced expression of p66ShcA but also demonstrated increased generation of ROS; whereas, p66ShcA-deficient podocytes showed attenuated generation of ROS. Based on these results we hypothesize that in HIV-1 infection, inhibition of p66ShcA activates a Foxo3A- dependent stress program that promotes the survival phenotype. We further hypothesize that deletion of p66ShcA from the genome of Tg26 mice will not only attenuate or prevent HIV-1-induced oxidative stress, but also delay or prevent the progression of renal lesions. In the present proposal we will 7 Test the hypothesis that inhibition of p66ShcA in HIV-1-infected podocytes activates a Foxo3-dependent stress program that promotes the survival phenotype 7 Test the hypothesis that deletion of p66ShcA from the genome of Tg26 mice will delay or prevent the progression of renal lesions 7 Test the hypothesis that HIV-1-induced p66ShcA redox function and dysregulation of the mTOR pathway leads to renal pathogenesis associated with HIVAN The outcome of these studies will help us in the development of therapeutic strategies to treat this devastating renal disease.

描述（由申请人提供）：人类免疫缺陷病毒相关的肾病（Hivan）是一个独特的临床病理学实体，其特征在于局灶性节段性肾小球硬化（FSGS）和微管菌病变。他人和美国的初步研究表明，HIV-1感染的许多作用是通过氧化应激介导的，这是由活性氧（ROS）产生的。最近，在氧化应激的产生中已经确定了p66SHCA蛋白的关键作用。本提案的长期目标是制定新颖的治疗策略，靶向突变基因或功能失调的基因产物，以阻止或防止Hivan的发展。我们最近在TG26（HIVAN小鼠）动物模型的初步研究表明，肾小球和管状细胞均显示出增强的ROS的产生。此外，在体外研究中，用HIV-1转导的足细胞不仅显示了P66SHCA的表达增强，而且还显示出ROS的产生增加。而P66SHCA缺陷型足细胞显示ROS的产生。基于这些结果，我们假设在HIV-1感染中，p66SHCA的抑制激活了促进生存表型的FOXO3A依赖性压力程序。我们进一步假设从TG26小鼠的基因组中缺失P66SHCA不仅会衰减或预防HIV-1诱导的氧化应激，而且还会延迟或阻止肾脏病变的发展。在本提案中，我们将7检验以下假设：HIV-1感染的足细胞中p66SHCA抑制p66SHCA激活了一个依赖FoxO3的压力计划，该计划促进了生存表型7检验的假设，即在TG26鼠的基因组中的p66shca的缺失将延迟或预防肾脏的进展。 MTOR途径的失调导致与Hivan相关的肾脏发病机理，这些研究的结果将有助于我们发展治疗这种毁灭性肾脏疾病的治疗策略。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HIVAN phenotype: consequence of epithelial mesenchymal transdifferentiation.

DOI：
10.1152/ajprenal.00415.2009
发表时间：
2010-03
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
A. Yadav;Sridevi Vallabu;Dileep Kumar;G. Ding;D. Charney;P. Chander;P. Singhal
通讯作者：
A. Yadav;Sridevi Vallabu;Dileep Kumar;G. Ding;D. Charney;P. Chander;P. Singhal

Ang II enhances tubular cell Ets-1 expression and associated down stream signaling is mediated through AT1 receptors.

Ang II 增强肾小管细胞 Ets-1 表达，相关下游信号传导通过 AT1 受体介导。

DOI：
10.3109/0886022x.2010.501936
发表时间：
2010
期刊：
Renal failure
影响因子：
3
作者：
Kumar,Dileep;Luan,Liming;Pathak,Shresh;Salhan,Divya;Magoon,Sandeep;Singhal,PravinC
通讯作者：
Singhal,PravinC

Rapamycin-induced modulation of HIV gene transcription attenuates progression of HIVAN.

DOI：
10.1016/j.yexmp.2012.09.009
发表时间：
2013-02
期刊：
EXPERIMENTAL AND MOLECULAR PATHOLOGY
影响因子：
3.6
作者：
Rai, Partab;Plagov, Andrei;Kumar, Dileep;Pathak, Shresh;Ayasolla, Kamesh R.;Chawla, Amrita K.;Mathieson, Peter W.;Saleem, Moin A.;Husain, Mohammad;Malhotra, Ashwani;Singhal, Pravin C.
通讯作者：
Singhal, Pravin C.

Nef interaction with actin compromises human podocyte actin cytoskeletal integrity.

Nef 与肌动蛋白的相互作用会损害人足细胞肌动蛋白细胞骨架的完整性。

DOI：
10.1016/j.yexmp.2012.06.001
发表时间：
2013
期刊：
Experimental and molecular pathology
影响因子：
3.6
作者：
Tan,Raymond;Patni,Hitesh;Tandon,Pranai;Luan,Liming;Sharma,Bipin;Salhan,Divya;Saleem,MoinA;Mathieson,PeterW;Malhotra,Ashwani;Husain,Mohammad;Upadhya,Poornima;Singhal,PravinC
通讯作者：
Singhal,PravinC

Hedgehog pathway plays a vital role in HIV-induced epithelial-mesenchymal transition of podocyte.