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

基本信息

批准号：
10304147
负责人：
Joel L Pomerantz
金额：
$ 43.64万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10304147
关键词：
Alleles Antigen Receptors Antigens B Cell Proliferation B-Cell Activation B-Cell Antigen Receptor B-Cell Lymphomas B-Lymphocytes Behavior Bromodomain Bypass CD69 antigen 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 Process Proteins Receptor Cell Receptor Signaling Role Sampling Scaffolding Protein Severity of illness Signal Pathway Signal Transduction Signaling Molecule Signaling Protein T-Cell Receptor T-Lymphocyte Testing Work 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&apos s lymphoma lymphocyte proliferation novel novel therapeutics pathogen prevent protein function receptor recruit scaffold therapy design

项目摘要

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，包括促进增殖和存活的基因。NF-κB 的不适当激活与多种因素相关。淋巴瘤，信号分子经常发生突变，从而引发其受体独立性 CARD11 是一种在 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，先前的工作已经证实，大约 10% 的 ABC DLBCL 患者样本中发现了该蛋白的过度激活。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将多个信号辅助因子募集到诱导 IKK 活性的复合物中。 CARD11 控制此转换；它使 CARD11 在基础状态下保持非活动状态，但接收来自参与中和其抑制作用并允许 CARD11 发出淋巴瘤相关信号的受体。 CARD11 突变绕过正常激活并将 CARD11 转化为组成型活性信号传导然而，人们对 CARD11 在正常抗原受体信号传导过程中的作用仍知之甚少。转化为活性状态时，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 细胞转化为淋巴瘤。在此应用中，我们将 1) 研究信号传导潜力和协作方式。突变决定致癌 CARD11 介导的体内异常 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传导；3) 剖析 CARD11 信号传导周期中几个步骤所需的决定因素。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。