Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator

关键信号整合器控制淋巴细胞激活和增殖的机制

• 批准号: 10528445
• 负责人: Joel L Pomerantz
• 金额: $ 49.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528445
• 关键词: Alleles; Antigen Receptors; Antigens; B Cell Proliferation; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Behavior; Bromodomain; Bypass; CRISPR screen; Cell Count; Cells; Complex; Critical Pathways; Development; Disease; Elements; Etiology; Genes; Genetic; Growth; Human; Immune; Immune response; Infection; Kinetics; Knock-in Mouse; Knockout Mice; Knowledge; Lesion; Leukocytes; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Molecular; Molecular Target; Mus; Mutation; Oncogenic; Output; Pathogenicity; Pathway interactions; Patients; Physiological; Predisposition; Process; Productivity; Proliferating; Proteins; Receptor Signaling; Role; Sampling; Scaffolding Protein; Severity of illness; Signal Induction; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; T-Cell Receptor; T-Lymphocyte; Testing; Work; activated B cell like; adaptive immune response; cell behavior; cofactor; design; gain of function; genome-wide; immune system function; improved; in vivo; inhibitor; insight; large cell Diffuse non-Hodgkin' s lymphoma; lymphocyte proliferation; novel; novel therapeutics; pathogen; prevent; protein function; receptor; recruit; scaffold; therapy design; transmission process

PROJECT SUMMARY/ABSTRACT Antigen receptor signaling to NF-κB is a highly regulated, critical pathway for B and T lymphocyte activation during the adaptive immune response. NF-κB controls many genes required for lymphocyte function including genes that promote proliferation and survival. The inappropriate activation of NF-κB is associated with multiple lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor-independent constitutive NF-κB activity. CARD11 is a key scaffold protein that functions in both T cell receptor and B cell receptor pathways to transmit signals from the engaged receptor to the activation of the IKK complex and NF- κB. Aberrant CARD11-dependent signaling is required for the dysregulated proliferation of the activated B cell- like (ABC) subtype of Diffuse Large B Cell Lymphoma (DLBCL), and mutations in CARD11, which hyperactivate the protein, are found in ~10% of patient samples of ABC DLBCL. Previous work has established that during normal signaling, CARD11 undergoes a transition from an inactive to an active signaling scaffold that recruits several signaling cofactors into a complex that induces IKK activity. An Inhibitory Domain (ID) in CARD11 controls this transition; it keeps CARD11 inactive in the basal state, but receives signals from the engaged receptor that neutralize its inhibitory action and allow CARD11 to signal. Lymphoma-associated mutations in CARD11 bypass normal activation and convert CARD11 into a constitutively active signaling scaffold. However, it remains poorly understood how during normal antigen receptor signaling CARD11 is converted to its active state, how precisely normal and oncogenic forms of CARD11 signal to the IKK complex to activate NF-κB, and how DLBCL-associated gain-of-function CARD11 alleles achieve the transformation of normal B cells into lymphoma. In this application we will 1) investigate how signaling potential and cooperating mutations determine the extent of oncogenic CARD11-mediated aberrant B cell proliferation in vivo; 2) investigate the role of a newly identified factor required for CARD11 activity in normal and oncogenic antigen receptor signaling; and 3) dissect determinants required for several steps in the CARD11 signaling cycle. Our studies will advance understanding of the mechanisms of antigen receptor signaling during lymphocyte activation, illuminate how signaling proteins, especially scaffolds, achieve signal-induced activation during normal physiological behavior, and improve our understanding of how the combination of genetic lesions found in lymphoma determines disease severity. Our studies should reveal a previously unrecognized molecular target for the development of new therapies designed to treat NF-κB-dependent cancers and other diseases that result from aberrant immune cell behavior.

项目概要/摘要 抗原受体信号传导至 NF-κB 是 B 和 T 淋巴细胞激活的高度调控的关键途径 在适应性免疫反应期间。 NF-κB 控制淋巴细胞功能所需的许多基因，包括 促进增殖和生存的基因。 NF-κB 的不当激活与多种因素有关 淋巴瘤，信号分子经常发生突变，从而引发其受体独立性 组成型 NF-κB 活性。 CARD11 是在 T 细胞受体和 B 细胞中发挥作用的关键支架蛋白 受体途径将信号从参与的受体传递到 IKK 复合物和 NF- 的激活 κB。异常的 CARD11 依赖性信号传导是激活 B 细胞增殖失调所必需的。 例如弥漫性大 B 细胞淋巴瘤 (DLBCL) 的 (ABC) 亚型，以及 CARD11 的突变， 过度激活该蛋白，在约 10% 的 ABC DLBCL 患者样本中发现。之前的工作已经建立 在正常信号传导过程中，CARD11 经历从非活性信号支架到活性信号支架的转变 它将多种信号辅助因子募集到诱导 IKK 活性的复合物中。抑制域 (ID) CARD11 控制此转换；它使 CARD11 在基础状态下保持非活动状态，但接收来自 接合受体，中和其抑制作用并允许 CARD11 发出信号。淋巴瘤相关 CARD11 突变绕过正常激活并将 CARD11 转化为组成型活性信号传导 脚手架。然而，人们对 CARD11 在正常抗原受体信号传导过程中如何发挥作用仍知之甚少。 转换为活性状态时，正常形式和致癌形式的 CARD11 向 IKK 复合体发出信号的精确程度 激活 NF-κB，以及 DLBCL 相关的功能获得性 CARD11 等位基因如何实现 正常B细胞​​转变为淋巴瘤。在此应用中，我们将 1) 研究信号潜力和协作如何 突变决定体内致癌性 CARD11 介导的异常 B 细胞增殖的程度； 2） 研究新发现的 CARD11 活性所需因子在正常和致癌抗原中的作用 受体信号转导； 3) 剖析 CARD11 信号循环中几个步骤所需的决定因素。我们的 研究将促进对淋巴细胞过程中抗原受体信号传导机制的理解 激活，阐明信号蛋白，特别是支架，如何在过程中实现信号诱导的激活 正常的生理行为，并提高我们对基因组合如何发现病变的理解 淋巴瘤的发生决定了疾病的严重程度。我们的研究应该揭示一种以前未被识别的分子 开发旨在治疗 NF-κB 依赖性癌症和其他疾病的新疗法的目标 这是由异常的免疫细胞行为引起的。