Regulation of Apoptosis in Renal Ischemia

肾缺血中细胞凋亡的调节

基本信息

批准号：
7984459
负责人：
BABU Joseph PADANILAM
金额：
$ 37.13万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984459
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Affect Apoptosis Apoptotic 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 TP53 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）：抑制细胞凋亡可防止缺血性肾损伤（IRI）。最近的报告表明，IRI 后抑制转录因子 p53 可防止细胞凋亡并改善肾功能；然而，p53诱导细胞凋亡的信号通路尚未阐明。我们确定了两个促凋亡 p53 转录靶点 Siva 和 PERP（与 PMP-22 相关的 p53 凋亡效应子）在 IRI 中被特异性激活。抑制 Siva 可防止小鼠细胞凋亡并提供针对 IRI 的功能保护。 Siva 的过度表达通过 caspase 依赖性和独立机制导致体外肾近端肾小管细胞 (PTC) 的凋亡细胞死亡。我们的长期研究目标是阐明调节 PTC 细胞凋亡的细胞信号传导途径，以确定干预这些途径治疗急性肾损伤 (AKI) 的策略。这项工作的目的是阐明 Siva 和 PERP 整合其信号以诱导肾 PTC 细胞凋亡并干预其信号通路以治疗 IRI 的机制。核心假设是，Siva 和 PERP 的激活通过 TNF 受体 CD27 刺激外源性凋亡途径，诱导线粒体通透性释放凋亡因子，并易位至细胞核招募凋亡诱导因子 (AIF)，从而在 IRI 后触发 PTC 凋亡。该假设的有效性将通过追求三个具体目标来测试，这些目标旨在确定 Siva-CD27 和 Siva-PERP 相互作用引发 caspase 依赖性和独立细胞凋亡的机制，并确定其信号传导在诱导细胞凋亡中的体内功能意义并损害肾缺血小鼠模型的肾功能。这些研究的意义包括确定了一种可能引发 PTC 细胞凋亡的新途径，这可能为干预提供新的机会，对 AKI 的预后和治疗都有重要的临床意义。公共卫生相关性：急性肾损伤是一种毁灭性的临床综合征，死亡率为 50%，影响着所有住院患者的 5-7%。目前，尚无公认的疗法可用于治疗这种情况。干扰 p53 介导的细胞凋亡程序可能有助于开发新的治疗策略来降低死亡率和发病率。后一种结果可能会对生活质量产生巨大影响，并降低与急性肾损伤相关的医疗费用。