Regulation of TNFa signaling

TNFa 信号传导的调节

• 批准号: 8708119
• 负责人: ANNING LIN
• 金额: $ 29.29万
• 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/8708119
• 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.

描述（由申请人提供）：我们的研究的长期目标是研究如何响应特定细胞外刺激的细胞内信号传导回路，从而确定预防和治疗人类疾病的潜在治疗靶标。在该提案中，我们将研究JNK信号中的新型信号和途径 - 特异性调节剂或调节剂（SMOR）的锌指蛋白Miz1的分子机制，选择性地调节了TNFalpha诱导的JNK活化以及该调节的病理生理含义。使用多方面的方法，我们最近发现MIZ1充当一种新型的信号和途径特异性调节剂或调节剂（SMOR），从而对TNFALPHA诱导的JNK激活进行负调节。 MIZ1抑制TNFALPHA诱导的TRAF2的K63连接的多泛素化，从而仅抑制TNFalpha的JNK，但不抑制ERK，p38或IKK的激活，仅抑制TNFALPHA的JNK激活，而不是通过TNFALPHA激活，而不是IL-1，UV，TPA，TPA，或其他JNK jnk。 TNFalpha刺激后，MIZ1经历泛素化和随后的蛋白酶体降解，从而缓解其抑制作用。我们假设MIZ1是TNF-R1复合物1的新成分，并且在调节TNFALPHA信号传导中起关键作用。该提议是新颖的，因为它将研究MIZ1如何作为TNF-R1复合物的新组成部分，以研究MIZ1是否确定TNFalphA-Acipted JNK和IKK之间的动力学差异，并确定MIZ1-介导的TNFALPHA SIGNLAAINGAINAINLAINGAINAINGINAL抑制的病理生理功能。这项研究将提出一个关于分子机制的新范式，该分子机制通过调节TNF-R1复合物的激活，并可以更好地了解TNF-α信号的分子基础调节，这在许多人类疾病中对炎症很重要。