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号（NOT-OD-09-058）而提交的：NIH 宣布恢复法案资金可用于竞争性修订申请。本竞争性修订 (CR) 申请的总体目标是检查 NF-kB 诱导激酶 (NIK) 调节 Th17 细胞分化和 EAE 诱导的信号传导机制。 Th17 细胞是 CD4 效应 T 细胞的一个子集，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是人类多发性硬化症（MS）的动物模型，阐明EAE发病机制的分子机制对于合理设计MS疗法具有重要意义。本 CR 申请中提出的研究基于我们的新发现，即 NIK 在调节 Th17 细胞分化和 EAE 诱导中具有关键作用。 NIK 是一种已知介导非经典 NF-kB 信号传导激活的激酶，涉及 NF-kB2 前体蛋白 p100 的磷酸化和蛋白酶体加工以及 p52/RelB NF-kB 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。我们发现 NIK 调节 Th17 细胞分化和 EAE 诱导，揭示了 NIK 的一项新颖且重要的功能。因此，本 CR 申请中提出的研究既有意义又具有创新性。 我们已经证明，NIK 缺陷的幼稚 CD4 T 细胞在 Th17 细胞分化中减弱，尽管它们能够分化为效应 T 细胞的其他亚群。我们进一步证明 NIK 在调节 Th17 分化和 EAE 诱导方面具有 T 细胞内在功能。有趣的是，我们的研究发现了 NIK 的一种新的信号传导功能，其中涉及关键 Th17 调节转录因子 STAT3 的激活。 NIK 通过 T 细胞受体和 IL-6 受体信号介导 STAT3 的协同激活。由于已知 STAT3 与 NF-kB 蛋白有物理相互作用并在功能上协同作用，因此我们假设 NIK 可能通过介导非经典 NF-kB 和 STAT3 的激活来调节 Th17 分化和 EAE 发病机制。我们将 (1) 确定 CD4 T 细胞中 NIK 介导的 STAT3 激活的机制和功能意义，(2) 检查非经典 NF-kB 在 Th17 分化和 EAE 发病机制调节中的作用，(3) 检查 TRAF3 在 NIK 调节和 Th17 细胞分化中的作用，以及 (4) 定义 NIK 的 Th17 调节功能所需的结构域/基序。 公共卫生相关性：实验性自身免疫性脑脊髓炎 (EAE) 是一种涉及炎症 T 细胞病理作用的多发性硬化症 (MS) 动物模型。了解EAE发病机制的分子机制对于合理设计MS疗法非常重要。该修订项目的目标是了解蛋白激酶 NIK 调节炎症 T 细胞产生和 EAE 发病机制的分子机制。