Regulation of TNFa signaling

TNFa 信号传导的调节

• 批准号: 8174966
• 负责人: ANNING LIN
• 金额: $ 28.06万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174966
• 关键词: Alleles; Apoptosis; Apoptosis Inhibitor; Caspase; Cell Death; Complex; Cytokine Signaling; Cytoplasm; Death Domain; Dissociation; Embryo; Genetic; Genetic Transcription; Goals; Immune response; Inflammation; Inflammatory; Interleukin-1; Kinetics; Knockout Mice; Light; Link; MAPK14 gene; MAPK8 gene; Mediating; Membrane; Modeling; Molecular; Mus; NF-kappa B; Occupations; Play; Polyubiquitination; Prevention; Protein Kinase; Proteins; Recruitment Activity; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Stimulus; TNF gene; TNF receptor-associated factor 2; TNFRSF1A gene; TRAF2 gene; Testing; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ubiquitination; Zinc Fingers; base; cytokine; extracellular; human RIPK1 protein; human TNF protein; human disease; in vivo; member; novel; prevent; receptor; response; therapeutic target; transcription factor

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 by which the zinc finger protein Miz1, a novel signal- and pathway- specific modulators or regulators (SMOR) in the JNK signalsome, selectively regulates TNFalpha-induced JNK activation and the pathophysiological implications of this regulation. Using multifaceted approaches, we have recently discovered that Miz1 acts as a novel signal- and pathway-specific modulators or regulators (SMOR) to negatively regulate TNFalpha- induced JNK activation. Miz1 suppresses TNFalpha-induced K63-linked polyubiquitination of TRAF2, thereby only inhibiting activation of JNK but not ERK, p38 or IKK by TNFalpha, and only JNK activation by TNFalpha but not IL-1, UV, TPA, or other JNK activators. Upon TNFalpha stimulation, Miz1 undergoes ubiquitination and subsequent proteasomal degradation, thereby relieving its inhibition. We hypothesize that Miz1 is a novel component of TNF-R1 Complex 1 and plays a critical role in regulation of TNFalpha signaling. This proposal is novel, as it will study how Miz1 functions as a novel component of TNF-R1 Complex 1, to study whether Miz1 determines the kinetic difference between TNFalpha- activated JNK and IKK, and to determine the pathophysiological functions of Miz1-mediated inhibition on the TNFalpha signlaing in vivo. This study will put forward a novel paradigm regarding the molecular mechanism by which activation of TNF-R1 Complex is regulated and will provide a better understanding of the molecular basis underlying regulation of TNF-alpha signaling, which is important in inflammation in many human diseases. PUBLIC HEALTH RELEVANCE: The pro-inflammatory cytokine tumor necrosis factor (TNFa) regulates immune responses, inflammation, and programmed cell death through activation of its downstream effectors such as NF-kB, JNK and caspases. Understanding how selective regulation of TNFa signaling by Miz1 should shed light on our understanding of molecular mechanism underlying activation of TNF1 receptor complex, which deregulation leads to 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点。在本提案中，我们将研究锌指蛋白 Miz1（JNK 信号体中的一种新型信号和通路特异性调节剂或调节剂 (SMOR)）选择性调节 TNFα 诱导的 JNK 激活的分子机制及其病理生理学意义。规定。通过多方面的方法，我们最近发现 Miz1 作为一种新型信号和通路特异性调节剂或调节剂 (SMOR) 来负向调节 TNFα 诱导的 JNK 激活。 Miz1 抑制 TNFα 诱导的 TRAF2 的 K63 连接多泛素化，从而仅抑制 TNFα 激活 JNK，但不抑制 ERK、p38 或 IKK；并且仅抑制 TNFα 激活 JNK，但不抑制 IL-1、UV、TPA 或其他 JNK 激活剂。在 TNFα 刺激下，Miz1 发生泛素化和随后的蛋白酶体降解，从而解除其抑制。我们假设 Miz1 是 TNF-R1 复合物 1 的新成分，在 TNFα 信号传导的调节中发挥关键作用。该提案是新颖的，因为它将研究Miz1如何作为TNF-R1复合物1的新成分发挥作用，研究Miz1是否决定TNFα激活的JNK和IKK之间的动力学差异，并确定Miz1介导的抑制的病理生理功能TNFα 体内信号传导。这项研究将提出一个关于调节 TNF-R1 复合物激活的分子机制的新范式，并将提供对 TNF-α 信号传导调节的分子基础的更好理解，该信号传导在许多人类疾病的炎症中非常重要。 公共健康相关性：促炎细胞因子肿瘤坏死因子 (TNFa) 通过激活其下游效应子（如 NF-kB、JNK 和半胱天冬酶）来调节免疫反应、炎症和程序性细胞死亡。了解 Miz1 如何选择性调节 TNFa 信号传导应该有助于我们理解 TNF1 受体复合物激活的分子机制，而这种失调会导致人类疾病。