Regulation of Apoptosis in Renal Ischemia

肾缺血中细胞凋亡的调节

• 批准号: 8117172
• 负责人: BABU Joseph PADANILAM
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/8117172
• 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; 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

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（由申请方提供）：抑制细胞凋亡可防止缺血性肾损伤（IRI）。最近的报道表明，抑制转录因子p53可以防止细胞凋亡，并改善IRI后的肾功能;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中特异性激活。抑制Siva可防止细胞凋亡，并在小鼠中提供功能性保护以防止IRI。Siva的过度表达通过半胱天冬酶依赖性和非依赖性机制导致体外培养的肾近端小管细胞（PTC）凋亡。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通路，以确定干预这些通路以治疗急性肾损伤（阿基）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。中心假设是Siva和PERP的激活通过TNF受体CD 27刺激外源性凋亡途径，诱导线粒体渗透性释放促凋亡因子并易位至细胞核以募集凋亡诱导因子（AIF），从而在IRI后触发PTC凋亡。将通过追求三个具体目标来测试该假设的有效性，这些目标旨在确定Siva-CD 27和Siva-PERP相互作用引起半胱天冬酶依赖性和非依赖性细胞凋亡的机制，并确定它们在肾缺血小鼠模型中诱导细胞凋亡和损害肾功能的信号传导的体内功能意义。这些研究的重要性包括确定了一种可能引发PTC凋亡的新途径，这可能为阿基的预后和管理提供具有重要临床意义的干预新机会。 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%，占所有住院患者的5-7%。目前，没有可接受的疗法可用于治疗这种情况。干扰p53介导的凋亡程序可能会允许开发新的治疗策略，以降低死亡率和发病率。后一种结果可能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。