Implications of Notch signaling in HIV associated nephropathy

Notch 信号传导在 HIV 相关肾病中的意义

基本信息

批准号：
9335836
负责人：
Madhulika Sharma
金额：
$ 15万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335836
关键词：
AIDS-Associated Nephropathy Adult Adverse effects Anemia Animal Model Apoptosis Binding Binding Sites Biopsy Blood capillaries Cell Nucleus Cell Proliferation Cells Choristoma Chronic Chronic Kidney Failure Dental Development Dilatation - action Disease Disease Progression Down-Regulation Drug resistance Effectiveness Epithelial Cells Epithelium Event Exhibits Feedback Focal Segmental Glomerulosclerosis Gastric Parietal Cells Gene Targeting Genes Genetic Goals HIV HIV-1 Highly Active Antiretroviral Therapy Histology Human Human Characteristics Hyperplasia In Vitro Incidence Kidney Kidney Diseases Kidney Failure Ligands Mediating Messenger RNA Metabolic syndrome Modeling Molecular Morbidity - disease rate Mus NPHS2 protein Neutropenia Parietal Pathogenesis Pathway interactions Patients Pharmacology Phenocopy Play Proteins Proteinuria Rattus Receptor Activation Recruitment Activity Renal function Renal glomerular disease Rodent Model Role Series Severity of illness Signal Transduction Testing Therapeutic Transactivation Transcription Factor AP-1 Treatment Efficacy Tubular formation Variant Viral capillary cell dedifferentiation disorder prevention gene product glomerulosclerosis in vivo inhibitor/antagonist kidney cell kidney epithelial cell knock-down mortality nef Protein nephrotoxicity notch protein podocyte prevent promoter public health relevance tat Protein transcription factor

项目摘要

DESCRIPTION (provided by applicant): Notch signaling has shown to play a key role in several kidney diseases, associated with glomerulosclerosis and podocyte apoptosis. However, its role in Human Immunodeficiency Virus Associated Nephropathy (HIVAN) which presents with collapsing variant of glomerulosclerosis, focal segmental glomerulosclerosis, and podocyte/parietal cell proliferation is not known. We used HIVAN patients and rodent models of HIVAN that express seven of the nine HIV genes and phenocopy most characteristics of HIVAN. We show that in contrast to other glomerular diseases, where Notch 1 and Notch2 receptor activation is predominant, Notch 4 pathway appeared to be most predominating in HIVAN. We found activated Notch4 expressed and elevated in podocytes, parietal epithelial cells and tubular epithelium. Pharmacological inhibition of Notch pathway in vivo ameliorated the disease progression in the Tg26 mice. Moreover podocyte proliferation induced by HIV proteins was inhibited by Notch inhibitors. These studies suggest that aberrant Notch signaling, contributes to the pathogenesis of HIVAN. In the first aim, we will determine the effects of podocyte and parietal cell specific genetic inhibition of Notch signaling on disease severity in Tg26 mice. In the second aim, we will perform in vitro studies from podocytes derived from Tg26 mice to determine the effect of Notch inhibition on podocyte proliferation, differentiation and apoptosis. We will also use parietal epithelial cells and podocytes to evaluate the possibility of interaction of Notch proteins with HIV-1 proteins. Finally in the third aim, we will genetically knockdown Notch4 in Tg26 mice and the possibility of disease prevention will be determined. These studies will provide: 1) a mechanism of Notch activation by HIV-1 and 2) a therapeutic platform to test Notch inhibitors in HIVAN patients.

描述（由适用提供）：Notch信号已显示在几种与肾小球硬化和足细胞凋亡有关的肾脏疾病中起关键作用。然而，其在人类免疫缺陷病毒相关的肾病（Hivan）中的作用尚不清楚，该肾病具有肾小球硬化，局灶性节段性肾小球硬化和足细胞/顶层细胞增殖的崩溃变体。我们使用了Hivan的Hivan患者和啮齿动物模型，这些模型表达了HIV基因中的七个，而表征则是Hivan的大多数特征。我们表明，与其他肾小球疾病相比，Notch 1和Notch2受体激活是主要的，Notch 4途径似乎在Hivan中最为占主导。我们发现活化的Notch4在足细胞，顶叶上皮细胞和管状上皮上皮细胞中表达并升高。体内缺口途径的药理抑制作用改善了TG26小鼠的疾病进展。此外，Notch抑制剂抑制了由HIV蛋白诱导的足细胞增殖。这些研究表明，异常的凹口信号传导有助于Hivan的发病机理。在第一个目的中，我们将确定足细胞和顶细胞特异性遗传抑制对Notch信号传导对TG26小鼠疾病严重程度的影响。在第二个目标中，我们将对来自TG26小鼠的足细胞进行体外研究，以确定Notch抑制对足细胞增殖，分化和凋亡的影响。我们还将使用顶叶上皮细胞和足细胞来评估Notch蛋白与HIV-1蛋白相互作用的可能性。最终，在第三个目标中，我们将在TG26小鼠中通常会敲除Notch4，并确定预防疾病的可能性。这些研究将提供：1）HIV-1和2）测试Hivan患者Notch抑制剂的缺口激活机制。