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：
10265763
负责人：
Carrie L. Lucas
金额：
$ 12.56万
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：
2020-08-14 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265763
关键词：
Antibodies Antibody Formation Antibody Response Asthma Autoimmune 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response peripheral blood polarized cell profiles in patients public health relevance response translational model unpublished works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 p110δ and p85α 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 PI3Kγ 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 PI3Kγ 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.

项目摘要原发性免疫缺陷疾病（PID）具有提供机械见解的巨大潜力分子和途径基本上对于维持人类免疫健康和无偏见重要对于正向遗传学的性质使这些研究特别令人兴奋（PI3K）信号通路在免疫内外的细胞行为的许多方面扮演进口角色系统。亚基在PID患者中已有细化，并阐明了基本的PI3K生物学和基础遗传性缺陷。人类疾病。我们的初步研究强调了其在免疫能力和组织炎症调节中的重要性我们称这种疾病已灭活PI3Kγ综合征（IPG）。 “肮脏”小鼠建模方法通过梳理遗传操纵和自然病原体暴露，将追求两个特定的目标1）定义PI3Kγ的作用 T细胞-Intrinsic和 - 超支信号调节T细胞激活和分化。抗体缺陷的机械基础。这个新颖的PID和PI3K信号通常会为了改善生理相关的基础 PID和其他人类疾病环境中翻译研究的模型。