Regulation of Apoptosis in Renal Ischemia

肾缺血中细胞凋亡的调节

基本信息

批准号：
8494039
负责人：
BABU Joseph PADANILAM
金额：
$ 29.44万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2010-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494039
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Affect Apoptosis Apoptotic BCL2 gene Binding Caspase Cell Death Cell Nucleus Cell membrane Cells Cessation of life Clinical Data Development Event Goals Health Care Costs Homeostasis Hybrids Hypoxia Impaired Renal Function In Vitro Inhibition of Apoptosis Injury Intervention Ischemia Kidney Knock-out Mediating Mitochondria Molecular Morbidity - disease rate Mus N-terminal Necrosis Organ Outcome Pathway interactions Patients Perfusion Permeability Play Primary Cell Cultures Process Proteins Public Health Quality of life Recruitment Activity Regulation Renal Tissue Renal function Reperfusion Injury Reporting Research Role Signal Pathway Signal Transduction Syndrome System TNFRSF6 gene Testing Tissues Transmembrane Domain Tubular formation Tumor Necrosis Factor Receptor Work Yeasts apoptosis inducing factor base caspase-8 cyclophilin D cytochrome c improved in vivo inhibitor/antagonist innovation insight kidney cell mortality mouse model mutant novel novel therapeutics nuclease outcome forecast prevent programs public health relevance receptor renal ischemia renal ischemia/hypoxia response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Inhibition of apoptosis protects against ischemic renal injury (IRI). Recent reports demonstrate that inhibition of the transcription factor p53 prevents apoptosis and improves renal function following IRI; however, the signaling pathways by which p53 induces apoptosis are yet to be elucidated. We identified two pro-apoptotic p53 transcriptional targets Siva and PERP (p53 apoptosis effector related to PMP-22) to be specifically activated in IRI. Inhibition of Siva prevented apoptosis and offered functional protection from IRI in mice. Over expression of Siva led to apoptotic cell death of renal proximal tubular cells (PTC) in vitro by caspase-dependent and independent mechanisms. Our long term research goal is to elucidate the cellular signaling pathways that regulate PTC apoptotic cell death, in order to identify strategies to intervene in those pathways to treat acute kidney injury (AKI). The objective of the proposed work is to delineate the mechanisms by which Siva and PERP integrate their signals to induce apoptosis in renal PTC and intervene in their signaling pathways to treat IRI. The central hypothesis is that activation of Siva and PERP stimulate the extrinsic apoptotic pathway via the TNF-receptor, CD27, induce mitochondrial permeability to release apoptogenic factors and translocate to the nucleus to recruit apoptosis inducing factor (AIF) to trigger PTC apoptosis post-IRI. The validity of the hypothesis will be tested by pursuing three specific aims that are aimed at determining the mechanisms by which Siva-CD27 and Siva- PERP interactions elicit caspase-dependent and independent apoptosis and determine the in vivo functional significance of their signaling in inducing apoptosis and impairing renal function in mouse model of renal ischemia. The significance of the studies includes the identification of a novel pathway that may initiate PTC apoptosis that may provide new opportunities for intervention with important clinical implications, both for prognosis and management of AKI. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a devastating clinical syndrome with a 50% mortality rate affecting 5-7% of all hospitalized patients. Currently, there are no accepted therapies available to treat this condition. Interfering with p53-mediated apoptotic programs may allow the development of novel therapeutic strategies to reduce the mortality and morbidity. The latter outcome could have a dramatic impact on the quality of life and reducing the health care cost associated with acute kidney injury.

描述（由申请人提供）：抑制细胞凋亡可预防缺血性肾损伤（IRI）。最近的报道表明，抑制转录因子p53可防止IRI后凋亡并改善肾功能。但是，p53诱导凋亡的信号传导途径尚未阐明。我们确定了在IRI中特异性激活的两个促凋亡P53转录靶标SIVA和PERP（p53凋亡效应子）。 SIVA的抑制可预防凋亡，并在小鼠中提供了IRI的功能保护。 SIVA的表达导致肾脏近端细胞（PTC）在体外通过caspase依赖和独立机制在体外的凋亡细胞死亡。我们的长期研究目标是阐明调节PTC凋亡细胞死亡的细胞信号传导途径，以确定干预治疗急性肾脏损伤（AKI）的途径的策略。拟议工作的目的是描述SIVA和PERP整合信号以诱导肾脏PTC中凋亡的机制，并干预其信号传导途径以治疗IRI。中心假设是，SIVA和PERP的激活通过TNF受体CD27刺激外部凋亡途径，诱导线粒体渗透性诱导凋亡因子并释放到细胞核中，并转移到核中以诱导PTC Apoptosis Post-iri。该假设的有效性将通过追求三个旨在确定Siva-CD27和Siva-Perp相互作用引起caspase依赖性和独立凋亡的机制来检验，并确定其信号的体内功能意义在引起肾脏和肾脏模型中降低肾脏模型的肾脏功能。研究的重要性包括鉴定出一种新的途径，该途径可能引发PTC凋亡，该途径可能为干预提供新的机会，并具有重要的临床意义，无论是对AKI的预后和管理。公共卫生相关性：急性肾脏损伤是一种毁灭性的临床综合征，死亡率为50％，影响了所有住院患者的5-7％。目前，尚无可用的治疗疗法来治疗这种情况。干扰p53介导的凋亡程序可能会允许发展新型的治疗策略，以降低死亡率和发病率。后一个结果可能会对生活质量产生巨大影响，并降低与急性肾脏损伤相关的医疗费用。