Mechanisms of immune dysregulation in human PI3Kgamma deficiency

项目摘要 原发免疫缺陷疾病(PID)具有巨大的潜力，可以提供对 分子和途径对维持人类免疫健康至关重要，而且不偏不倚 正向遗传学的性质使这些研究特别令人兴奋。磷脂酰肌醇3-激酶 (PI3K)信号通路在免疫内外细胞行为的许多方面发挥着重要作用 系统。编码p110δ和p85αPI3K基因的功能获得突变和功能丧失突变 已经在PID患者中发现了亚基，并阐明了PI3K的基本生物学和基础 遗传性免疫缺陷。然而，其他PI3K基因的突变还没有在遗传性中被描述 人类疾病。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，并且 我们的初步研究强调了它在免疫活性和组织炎症调节中的重要性。 这种疾病我们称之为失活的PI3Kγ综合征(IPGs)。使用原代人类细胞和尖端技术 通过结合基因操作和基因操作来重现人类疾病的“脏”小鼠建模方法 自然病原体暴露，将追求两个具体目标。目的1)确定PI3Kγ在调节中的作用 T细胞-调节T细胞激活和分化的内在和外在信号。目标2)解剖 抗体缺陷的机制基础。这些调查的结果将为 这一新的PID和PI3K信号总体上并将为提高生理相关性奠定基础 PIDs和其他人类疾病背景下的转化性研究模型。

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.