Mechanisms of immune dysregulation in human PI3Kgamma deficiency

人类 PI3Kgamma 缺乏症免疫失调的机制

基本信息

批准号：
9896405
负责人：
Carrie L. Lucas
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-24 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896405
关键词：
Antibodies Antibody Formation Antibody Response Asthma Autoimmune Process Autoimmune hemolytic anemia Autoimmunity BLR1 gene Binding Biochemical Biology CD3 Antigens CD4 Positive T Lymphocytes CXCL10 gene CXCL9 gene CXCR3 gene Catalytic Domain Cell Line Cells Chemotactic Factors Clinical Complex Critical Pathways Defect Development Disease Equilibrium Exhibits Exposure to G-Protein-Coupled Receptors Genes Genomic DNA Goals Housing Human Human Biology Hypersensitivity Immune Immune System Diseases Immune system Immunocompetence Immunologic Deficiency Syndromes In Vitro Individual Infection Infiltration Inflammation Inflammatory Inherited Interleukin-12 Investigation Letters Leukocytes Light Link Loss of Heterozygosity Lung Lymphocyte Maintenance Modeling Mononuclear Mus Mutation Myeloid Cells Nature PASLI disease PIK3CG gene Pathologic Pathway interactions Patients Pattern Phagocytes Phenotype Phosphatidylinositols Phosphotransferases Physiological Play Process Production Proteins Reporting Resources Role Serum Signal Pathway Signal Transduction Stimulus Structure of germinal center of lymph node Syndrome T cell differentiation T cell response T-Cell Activation T-Lymphocyte Testing Th1 Cells Therapeutic Tissues Translational Research Tumor-infiltrating immune cells Work cell behavior chemokine clinical phenotype congenital immunodeficiency cytokine cytopenia exome sequencing forward genetics gain of function gain of function mutation genetic manipulation human disease human model hypogammaglobulinemia immune health immunoregulation improved in vivo innovation insight interleukin-23 loss of function mutation macrophage monocyte mouse model next generation sequencing novel pathogen pathogen exposure patient response peripheral blood polarized cell profiles in patients public health relevance response translational model unpublished works

项目摘要

Project Summary Primary immunodeficiency diseases (PIDs) have great potential to provide mechanistic insights into the molecules and pathways fundamentally important for maintenance of human immune health, and the unbiased nature of forward genetics makes these studies particularly exciting to pursue. The phosphoinositide 3-kinase (PI3K) signaling pathway plays important roles in many aspects of cell behavior within and outside the immune system. Both gain-of-function and loss-of-function mutations in the genes encoding the p110 and p85 PI3K subunits have been identified in PID patients and have shed light on basic PI3K biology and underpinnings of inherited immunodeficiency. However, no mutations in the other PI3K genes have been described in inherited human disorders. We have now identified novel loss-of-function mutations in a new PI3K gene, PIK3CG, and our preliminary studies highlight its importance in immune competence and regulation of tissue inflammation in this disorder we have termed Inactivated PI3K Syndrome (IPGS). Using primary human cells and cutting-edge `dirty' mouse modeling approaches that recapitulate human disease by combining genetic manipulation and natural pathogen exposure, two specific aims will be pursued. Aim 1) To define the roles for PI3K in regulating T cell-intrinsic and -extrinsic signals that modulate T cell activation and differentiation. Aim 2) To dissect the mechanistic basis for antibody defects. The results of these investigations will provide significant insights into this novel PID and PI3K signaling in general and will lay the groundwork to improve physiologically relevant models for translational research in PIDs and other human disease contexts.

项目概要原发性免疫缺陷疾病（PID）具有巨大的潜力，可以为我们提供机制方面的见解。对维持人类免疫健康至关重要的分子和途径，以及公正的正向遗传学的性质使得这些磷酸肌醇 3-激酶研究特别令人兴奋。 (PI3K) 信号通路在免疫系统内外细胞行为的许多方面发挥着重要作用编码 p110 和 p85 PI3K 的基因中的功能获得和功能丧失突变。 PID 患者中已鉴定出 PI3K 亚基，并揭示了 PI3K 的基本生物学和基础然而，其他 PI3K 基因的突变尚未在遗传性免疫缺陷中被描述。我们现在已经在新的 PI3K 基因 PIK3CG 中发现了新的功能丧失突变。我们的初步研究强调了它在免疫能力和组织炎症调节中的重要性我们使用原代人类细胞和尖端技术将这种疾病称为失活 PI3K- 综合征 (IPGS)。 “肮脏”小鼠建模方法通过结合基因操作和自然病原体暴露，将追求两个具体目标 1) 明确 PI3K 在调节中的作用。调节 T 细胞活化和分化的 T 细胞内在和外在信号。目标 2) 剖析这些研究的结果将为抗体缺陷的机制基础提供重要的见解。这种新颖的 PID 和 PI3K 信号传导总体而言将为改善生理相关性奠定基础 PID 和其他人类疾病背景下的转化研究模型。