Mechanistic elucidation of pathogenic CBM complex mutations associated with atopic disease

与特应性疾病相关的致病性 CBM 复合体突变的机制阐明

• 批准号: 10737122
• 负责人: Joshua D. Milner
• 金额: $ 71.47万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737122
• 关键词: Affect; Allergic; Allergic Disease; Antigen Receptors; Asthma; Atopic Dermatitis; Attenuated; Automobile Driving; B-Lymphocytes; BCL10 gene; Biochemical; Biochemical Pathway; Cell Line; Cell Signaling Process; Cell physiology; Cell surface; Cells; Child; Chronic; Code; Collection; Communication; Complex; Coupled; Data; Defect; Developed Countries; Development; Diagnosis; Diagnostic; Disease; Dominant-Negative Mutation; Eczema; Effector Cell; Essential amino acids supplementation; Food Hypersensitivity; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Glean; Glutamine; Heterozygote; Human; Hypersensitivity; IgE; Immune; Immune System Diseases; Immune response; Immunology; Impairment; In Vitro; Individual; Infectious Skin Diseases; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-4; Intervention; Investigation; Knowledge; Lesion; Leukocytes; Ligation; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoma; MAPK8 gene; Maintenance; Metabolic Pathway; Molecular; Molecular Abnormality; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutant Strains Mice; Mutation; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Process; Production; Proliferating; Proteins; Receptor Signaling; Recording of previous events; Research; Resources; Respiratory Tract Infections; Role; STAT3 gene; STAT5B gene; Severe Combined Immunodeficiency; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Structure; Supplementation; System; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transfection; Transplantation; Validation; Variant; Work; adaptive immune response; allergic response; atopy; clinical phenotype; cohort; cytokine; gain of function mutation; genetic analysis; genome wide association study; in vivo; innovation; insight; interest; new therapeutic target; novel; null mutation; scaffold; skin barrier; tool; treatment strategy; uptake

PROJECT ABSTRACT The study of primary atopic disorders (PADs) has provided important and surprising knowledge about specific genes that control the function of white blood cells involved in driving allergic responses. Over the last several years, our groups have played a leading role in the discovery and characterization of human immune disorders linked to mutations in CARD11, which encodes a critical signaling protein in lymphocytes. CARD11 partners with two other proteins (BCL10 and MALT1) to form the “CBM complex”, which communicates key signals that dictate lymphocyte activation, differentiation and function. Most recently, we described numerous patients with severe eczema, asthma/food allergies, and skin/respiratory infections that carried debilitating CARD11 mutations that disrupt normal CBM function. These variants attenuate CBM signaling in patient lymphocytes and cause them to differentiate abnormally into effector cells associated with allergy/atopy. The long-term objective of this project is to precisely define which cell signaling processes are disrupted by mutations in CBM complex genes, and elucidate how these defects adversely affect B and T cell function to ultimately manifest as in atopy, including assessment of glutamine as a potential treatment strategy. We will also define the broader scope and burden of pathogenic CBM complex mutations that influence atopic predisposition in both rare PADs and common cohorts of allergy disease patients. Built upon an extensive panel of atopy-associated, damaging mutations spanning the CARD11 gene, and extending to other CBM gene mutations identified from allergic patient cohorts, our studies will better define how these mutations disrupt normal CBM-dependent signaling pathways in lymphocytes. Using well- established cell transfection systems AND primary murine and patient cells, we will elucidate the molecular and cellular mechanisms through which impaired CARD11 signaling drives the preferential production of allergy- associated cytokines and IgE. Based on compelling preliminary data, our analyses will pinpoint specific biochemical and metabolic pathways that are disrupted by defective CARD11 signaling directly in primary cells from affected patients, an invaluable resource that we have unique access to. Defining these molecular abnormalities will enhance our understanding of disease pathogenesis and illuminate mechanisms by which simple interventions, such as supplementation with the essential amino acid glutamine, can restore the proper function of T and B cells harboring CBM mutations. Our innovative approach has the potential to significantly revise our understanding of how the CBM complex regulates adaptive immune responses. Insights gleaned from a more thorough investigation of CBM gene mutations, derived from both rare and common allergy patient cohorts, will better define their contribution to atopic susceptibility and inform new targeted therapeutic approaches for treating a broader spectrum of patients suffering from allergic disease.

项目摘要 对原发性疾病（PAD）的主要研究提供了有关的重要而令人惊讶的知识 控制涉及驱动过敏反应的白细胞功能的特定基因。最后 几年，我们的小组在人类免疫的发现和表征中发挥了领导作用 与Card11突变有关的疾病，该突变编码淋巴细胞中的关键信号蛋白。卡11 与另外两种蛋白质（BCL10和MALT1）的合作伙伴形成“ CBM综合体”，该蛋白会传达密钥 决定淋巴细胞激活，分化和功能的信号。最近，我们描述了许多事情 严重的湿疹，哮喘/食物过敏以及皮肤/呼吸道感染的患者使人衰弱 破坏正常CBM功能的Card11突变。这些变体减弱了患者的CBM信号 淋巴细胞并导致它们将绝对性分化为与过敏/定性相关的效应细胞。这 该项目的长期目标是精确定义哪些细胞信号传导过程被破坏 通过CBM复合基因中的突变，并阐明了这些缺陷如何不利影响B和T细胞 功能最终像应特应当一样表现出来，包括评估谷氨酰胺作为潜在的治疗 战略。我们还将定义致病性CBM复合物突变的更广泛的范围和燃烧 在过敏疾病患者的稀有垫和常见人群中影响特定易感性。 建立在广泛的与Anopy相关的，有害的突变的基础上，跨越Card11基因 并扩展到从过敏患者队列中鉴定出的其他CBM基因突变，我们的研究将更好 定义这些突变如何破坏淋巴细胞中正常的CBM依赖性信号通路。使用 建立的细胞转染系统以及原发性鼠和患者细胞，我们将阐明分子和 Card11信号传导损害的细胞机制驱动了过敏的首选产生 相关的细胞因子和IgE。基于引人注目的初步数据，我们的分析将确定特定 生化和代谢途径被直接在原代细胞中的Card11信号破坏的生化和代谢途径 来自受影响的患者，这是我们独特访问的宝贵资源。定义这些分子 异常将增强我们对疾病发病机理的理解和照亮机制 简单的干预措施，例如补充必需氨基酸谷氨酰胺，可以恢复适当的 具有CBM突变的T和B细胞的功能。我们的创新方法有可能显着 修改我们对CBM复合物如何调节适应性免疫回报的理解。见解收集 来自对CBM基因突变的更彻底的研究，这些突变均来自稀有和常见过敏 患者队列将更好地定义其对特征性敏感性的贡献，并告知新的目标疗法 治疗更广泛患有过敏性疾病的患者的方法。

项目成果

ERBIN and phosphoglucomutase 3 deficiency.

• DOI: 10.1016/j.coi.2023.102353
• 发表时间: 2023-06
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: J. Milner