Regulation of Apoptosis in Renal Ischemia

描述(由申请人提供)：抑制细胞凋亡可保护肾脏免受缺血性肾损伤(IRI)。最近的研究表明，抑制转录因子P53可防止肾缺血再灌注后的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不清楚。我们确定了两个促凋亡的P53转录靶点SIVA和PERP(与PMP-22相关的P53凋亡效应因子)在IRI中被特异性激活。抑制SIVA可阻止小鼠的细胞凋亡，并提供对IRI的功能保护。SIVA的过度表达可通过caspase依赖和独立的机制诱导体外培养的肾小管上皮细胞(PTC)的凋亡。我们的长期研究目标是阐明调控PTC细胞凋亡的细胞信号通路，以确定干预这些通路治疗急性肾损伤(AKI)的策略。本研究的目的是阐明SIVA和PERP整合其信号以诱导肾PTC细胞凋亡并干预其治疗IRI的信号通路的机制。中心假说是SIVA和PERP的激活通过肿瘤坏死因子受体CD27刺激外源性凋亡途径，诱导线粒体通透性释放促凋亡因子，并移位到细胞核募集凋亡诱导因子(AIF)，从而触发PTC在IRI后的凋亡。这一假说的有效性将通过追求三个特定的目标来检验，这三个目标旨在确定SIVA-CD27和SIVA-PERP相互作用诱导caspase依赖和独立的细胞凋亡的机制，并确定它们的信号在诱导小鼠肾缺血模型细胞凋亡和损害肾功能中的体内功能意义。这些研究的意义包括发现一条可能启动PTC凋亡的新途径，该途径可能为干预提供新的机会，对AKI的预后和治疗具有重要的临床意义。 公共卫生相关性：急性肾损伤是一种破坏性的临床综合征，50%的死亡率影响到5-7%的住院患者。目前，还没有公认的治疗这种疾病的方法。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重大影响，并降低与急性肾损伤相关的医疗保健成本。

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.