Mechanism of IKK Signaling Network

IKK信号网络机制

• 批准号: 8670762
• 负责人: ANNING LIN
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-07 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670762
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; BCL2 gene; Bad protein; Binding; Biological Process; Cell Death; Cell Survival; Cessation of life; Complex; Cytoplasm; Cytoplasmic Protein; Data; Glycolysis; Goals; Growth Factor; Immune response; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Interleukin-3; Light; Mediating; Mitochondria; Modeling; Molecular; Molecular Probes; Mus; Necrosis; Phosphorylation; Phosphotransferases; Play; Prevention; Protein Family; Protein Kinase; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stimulus; TNF gene; Testing; Tumor Necrosis Factor-alpha; Withdrawal; cell growth; cytokine; extracellular; human disease; in vivo; mutant; novel; public health relevance; response; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism underlying the IKK signaling network and its pathophysiological implications, using regulation of Bad by IKK in TNF¿-induced apoptosis as a molecular probe. Using multifaceted approaches, we uncovered a second signaling pathway of the IKK signaling network, i.e., the IKK-Bad axis. We found that Bad is a novel target of IKK and is also required for TNF¿-induced apoptosis in vitro and in vivo. Regulation of Bad by IKK is involved in inhibition of TNF¿-induced apoptosis. We hypothesize that in addition to activation of NF-?B, IKK inhibits TNF¿-induced apoptosis via inactivation of Bad, i.e., the "NF-?B activation and Bad inactivation" model. This proposal is novel, as it will study the role of the IKK-Bad axis in apoptosis induced by TNF¿ and other death stimuli, as well as in necrosis and autophagy, and the underlying mechanism and pathophysiological functions of the regulation in vitro and in vivo. This study will put forward a novel paradigm regarding the IKK signaling network and will provide a better understanding of the biological functions of the IKK signaling network in terms of regulation of cell death, which plays an important role in many human diseases.

描述（由适用提供）：我们研究的长期目标是研究如何响应特定的细胞外刺激，从而确定预防和治疗人类疾病的潜在治疗靶标。在此提案中，我们将使用IKK在TNF诱导的分子探针中对IKK的BAD调节，研究IKK信号网络及其病理生理学意义的分子机制。使用多方面方法，我们发现了IKK信号网络的第二个信号通路，即IKK-BAD轴。我们发现BAD是IKK的新目标，也是TNF®诱导的体外和体内凋亡所必需的。 IKK对BAD的调节参与了TNF®诱导的凋亡的抑制。我们假设除了激活NF-？B外，IKK还通过灭活不良，即“ NF-？B激活和不良失活”模型抑制TNF诱导的凋亡。该提案是新颖的，因为它将研究IKK-BAD轴在TNF和其他死亡刺激以及坏死和自噬中引起的凋亡中的作用，以及在体外和体内调节的基本机制和病理生理功能。这项研究将提出有关 IKK信号网络将在调节细胞死亡方面更好地了解IKK信号网络的生物学功能，这在许多人类疾病中起着重要作用。