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: 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
• 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' s lymphoma; lymphocyte proliferation; novel; novel therapeutics; pathogen; prevent; protein function; receptor; recruit; scaffold; therapy design

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.

项目摘要/摘要 NF-κB的抗原受体信号传导是B和T淋巴细胞激活的高度调节的关键途径 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 促进增殖和生存的基因。 NF-κB的不当激活与多个有关 淋巴瘤经常在信号分子中获取突变，从而引发其无关接收器 组成型NF-κB活性。 Card11是一种在T细胞受体和B细胞中起作用的关键支架蛋白 受体途径从参与受体传输信号到IKK复合物的激活和NF-的激活 κB。异常的Card11依赖性信号传导是激活B细胞扩散失调所必需的 像（ABC）弥漫性大B细胞淋巴瘤（DLBCL）的亚型，以及Card11中的突变， 在约10％的ABC DLBCL样品中发现了蛋白质过度活化。以前的工作已经建立 在正常信号传导期间，Card11经历了从无效到活动信号支架的过渡 这将几个信号辅助因子募集到一个诱导IKK活性的复合物中。抑制域（ID） 卡11控制此过渡；它使Card11处于基本状态，但从 接合中和其抑制作用并允许Card11发出信号的受体。淋巴瘤相关 Card11中的突变绕过正常激活，并将Card11转换为组成型主动信号传导 脚手架。但是，在正常的抗原受体信号传导卡11中，它仍然不足以了解 转换为其活性状态，card11信号的正常和致癌形式如何转换为IKK复合物 激活NF-κB，以及如何与DLBCL相关的功能收益Card11等位基因实现转化 正常B细胞​​进入淋巴瘤。在此应用程序中，我们将1）调查信号传导潜力和合作如何 突变决定了体内致癌Card11介导的异常B细胞增殖的程度； 2） 研究卡11活性在正常和致癌抗原中所需的新确定的因子的作用 接收器信号传导； 3）在Card11信号周期中的几个步骤所需的剖析确定。我们的 研究将提高对淋巴细胞中抗原受体信号传导机制的理解 激活，阐明信号蛋白，尤其是支架的信号蛋白如何实现信号诱导的激活 正常的身体行为，并提高我们对遗传病变的组合的理解 在淋巴瘤中决定疾病的严重程度。我们的研究应揭示先前未识别的分子 开发旨在治疗NF-κB依赖性癌症和其他疾病的新疗法的靶标 这是由异常的免疫细胞行为产生的。