Mechanisms of immune dysregulation in human PI3Kgamma deficiency

项目摘要 原发性免疫缺陷病（PID）具有很大的潜力，可以提供对免疫缺陷机制的深入了解。 分子和途径对维持人类免疫健康至关重要， 正向遗传学的性质使这些研究特别令人兴奋。磷酸肌醇3-激酶 （PI 3 K）信号通路在免疫内外细胞行为的许多方面起着重要作用。 系统编码p110δ和p85α PI 3 K基因的功能获得性和功能丧失性突变 亚基已经在PID患者中鉴定，并揭示了基本的PI 3 K生物学和 遗传性免疫缺陷然而，在其他PI 3 K基因中没有突变被描述为遗传性的。 人类疾病我们现在已经在一个新的PI 3 K基因PIK 3CG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， 我们将这种疾病称为失活PI 3 K γ综合征（IPGS）。利用原代人体细胞和尖端技术 “脏”小鼠建模方法，通过结合遗传操作和 自然病原体暴露，将追求两个具体目标。目的：1）明确PI 3 K γ在细胞凋亡调控中的作用， 调节T细胞活化和分化的T细胞内在和外在信号。目的2）解剖 抗体缺陷的机制基础。这些调查的结果将提供重要的见解， 这种新的PID和PI 3 K信号一般，并将奠定基础，以改善生理相关的 在PID和其他人类疾病背景下的转化研究模型。

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.