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（由申请人提供）：我们研究的长期目标是研究细胞内信号传导电路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。将利用 IKK 在 TNF 中对 Bad 的调节来研究 IKK 信号网络的分子机制及其病理生理学意义。 -诱导细胞凋亡作为分子探针，我们发现了 IKK 信号网络的第二条信号通路，即 IKK-Bad 轴，我们发现 Bad 是 IKK 的新靶标，也是 TNF 所必需的。 -IKK 对 Bad 的体外和体内诱导细胞凋亡参与了 TNF 的抑制。 -诱导细胞凋亡。我们认为除了激活 NF-κB 之外，IKK 还抑制 TNF¿ -通过 Bad 失活诱导细胞凋亡，即“NF-κB 激活和 Bad 失活”模型。该提议是新颖的，因为它将研究 IKK-Bad 轴在 TNF 诱导细胞凋亡中的作用。和其他死亡刺激，以及坏死和自噬，以及体外和体内调节的潜在机制和病理生理功能。 IKK信号网络将有助于更好地理解IKK信号网络在细胞死亡调节方面的生物学功能，细胞死亡在许多人类疾病中发挥着重要作用。