Molecular Mechanisms Regulating Noncanonical NF-kB Signaling

调节非典型 NF-kB 信号传导的分子机制

• 批准号: 7807470
• 负责人: Shao-Cong Sun
• 金额: $ 61.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807470
• 关键词: Animal Model; Attenuated; Autoimmune Diseases; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Maturation; Cells; Complex; Development; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Foundations; Funding; Goals; Human; Inflammatory; Interleukin 6 Receptor; Knockout Mice; Lymphoid; Mediating; Molecular; Multiple Sclerosis; NF-kappa B; Nuclear Translocation; Organ; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Production; Protein Kinase; Protein Precursors; Proteins; Receptor Signaling; Recovery; Regulation; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Solid; T-Cell Receptor; T-Lymphocyte; TNF receptor-associated factor 3; United States National Institutes of Health; base; design; immune function; innovation; novel; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): This application is submitted in response to the Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The overall objective of this Competitive Revision (CR) application is to examine the signaling mechanism by which the NF- kB-inducing kinase (NIK) regulates Th17 cell differentiation and EAE induction. Th17 cells are a subset of CD4 effector T cells critically involved in autoimmune diseases, particularly experimental autoimmune encephalomyelitis (EAE). Since EAE is an animal model of human multiple sclerosis (MS), elucidation of the molecular mechanism of EAE pathogenesis is important for rational design of MS therapies. The studies proposed in this CR application are based on our novel finding that NIK has a pivotal role in regulating Th17 cell differentiation and EAE induction. NIK is a kinase known to mediate activation of noncanonical NF-kB signaling, which involves phosphorylation and proteasomal processing of the NF-kB2 precursor protein, p100, and nuclear translocation of the p52/RelB NF-kB complex. Although NIK is known for its role in regulating B-cell maturation and lymphoid organ development, how NIK regulates T-cell effector function is poorly understood. Our finding that NIK regulates Th17 cell differentiation and EAE induction uncovers a novel and important function of NIK. Thus, the studies proposed in this CR application are both significant and innovative. We have shown that NIK-deficient naive CD4 T cells are attenuated in Th17 cell differentiation, although they are competent in differentiating to other subsets of effector T cells. We have further demonstrated that NIK has a T-cell intrinsic function in regulating Th17 differentiation and EAE induction. Interestingly, our studies identified a novel signaling function of NIK, which involves activation of a key Th17-regulatory transcription factor, STAT3. NIK mediates synergistic activation of STAT3 by the T-cell receptor and IL-6 receptor signals. Since STAT3 is known to physically interact with and functionally cooperate with NF-kB proteins, we hypothesize that NIK may regulate Th17 differentiation and EAE pathogenesis by mediating activation of both noncanonical NF-kB and STAT3. We will (1) determine the mechanism and functional significance of NIK-mediated STAT3 activation in CD4 T cells, (2) examine the role of noncanonical NF-kB in the regulation of Th17 differentiation and EAE pathogenesis, (3) examine the role of TRAF3 in NIK regulation and Th17 cell differentiation, and (4) define the domains/motifs of NIK that are required for its Th17-regulatory function. PUBLIC HEALTH RELEVANCE: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that involves pathological actions of inflammatory T cells. Understanding the molecular mechanism of EAE pathogenesis is very important for rational design of MS therapies. The goal of this revision project is to understand the molecular mechanism by which a protein kinase, NIK, regulates inflammatory T-cell production and EAE pathogenesis.

描述（由申请人提供）：本申请是为了响应通知编号（NOT-OD-09-058）而提交的：NIH宣布为竞争性修订申请提供恢复法案资金。本竞争性修订（CR）申请的总体目标是检查NF-κ B诱导激酶（NIK）调节Th 17细胞分化和EAE诱导的信号传导机制。Th 17细胞是CD 4效应T细胞的一个亚群，与自身免疫性疾病，特别是实验性自身免疫性脑脊髓炎（EAE）密切相关。由于EAE是人类多发性硬化（MS）的动物模型，阐明EAE发病机制的分子机制对于MS治疗的合理设计是重要的。本CR申请中提出的研究是基于我们的新发现，即NIK在调节Th 17细胞分化和EAE诱导中具有关键作用。NIK是已知介导非经典NF-κ B信号传导激活的激酶，其涉及NF-κ B 2前体蛋白p100的磷酸化和蛋白酶体加工以及p52/RelB NF-κ B复合物的核转位。尽管NIK因其在调节B细胞成熟和淋巴器官发育中的作用而闻名，但人们对NIK如何调节T细胞效应器功能知之甚少。我们的发现，NIK调节Th 17细胞分化和EAE诱导揭示了一个新的和重要的功能NIK。因此，本CR申请中提出的研究具有重要意义和创新性。 我们已经表明，NIK缺陷型幼稚CD 4 T细胞在Th 17细胞分化中减弱，尽管它们有能力分化为效应T细胞的其他亚群。我们进一步证明了NIK在调节Th 17分化和EAE诱导中具有T细胞内在功能。有趣的是，我们的研究确定了NIK的一种新的信号传导功能，其涉及关键的Th 17调节转录因子STAT 3的激活。NIK通过T细胞受体和IL-6受体信号介导STAT 3的协同活化。由于STAT 3是已知的物理相互作用和功能合作与NF-κ B蛋白，我们假设，NIK可能调节Th 17分化和EAE的发病机制，通过介导激活的非经典NF-κ B和STAT 3。我们将（1）确定NIK介导的STAT 3在CD 4 T细胞中激活的机制和功能意义，（2）检查非经典NF-kB在调节Th 17分化和EAE发病机制中的作用，（3）检查TRAF 3在NIK调节和Th 17细胞分化中的作用，以及（4）确定NIK的结构域/基序，其Th 17调节功能所需。 公共卫生相关性：实验性自身免疫性脑脊髓炎（EAE）是涉及炎性T细胞的病理作用的多发性硬化（MS）的动物模型。了解EAE发病的分子机制对合理设计MS治疗方案具有重要意义。本修订项目的目标是了解蛋白激酶NIK调节炎性T细胞产生和EAE发病机制的分子机制。