X chromosome, injury and infection

描述(由申请人提供)：与男性相比，女性在受伤和感染后表现出更好的一般健康状况、更长的寿命和更好的临床病程。人们普遍认为，女性的优势与性激素的影响有关。这个项目将测试X染色体连接蛋白变体在雌性体内的细胞嵌合体的存在是否代表了一种在宿主对感染的反应中有利的功能适应性细胞系统。来自女性的细胞携带双亲X染色体(母体XM和父系XP)，而男性只携带一条来自母亲(XM)的X染色体。由于剂量补偿和随机X失活，一半的雌性细胞分别表达来自XM或XP的蛋白质。因此，雌性是X连锁多态蛋白的细胞嵌合体。X染色体上有几个编码与先天性免疫反应有关的关键调节和代谢蛋白的基因。研究集中在两个X连锁蛋白上，第一，gp91Phox(Cybb)是NADPH氧化酶复合体的关键蛋白成分，产生杀菌所需的超氧阴离子；第二，IRAK1(IL-1受体相关激酶-1)是TLR介导的细胞信号通路的重要组成部分。这项研究将使用内毒素血症和败血症的实验模型，利用携带这些X连锁蛋白的遗传沉默形式的小鼠菌株。在脓毒症或内毒素血症后，将检测血液和骨髓细胞成分的变化以及吞噬细胞对肺、脾和肝脏的渗透。观察结果将在马赛克和单种群人/半合子缺陷或WT动物之间进行比较。还将测定和比较细胞信号、细胞因子产生和依赖氧化还原的细胞功能的变化。我们假设，女性马赛克患者将表现出急性异质性功能适应，这与败血症或内毒素血症后预后的改善有关。这将反映在细胞组成和细胞激活向马赛克亚群倾斜，表达有利的等位基因，以及改善细菌杀灭和存活率。这些研究将扩大我们对X染色体嵌合体和性别对免疫调节的细胞和生化机制的理解，并可能为治疗危重病开辟新的视角。与公共卫生相关：个体基因构成的微小差异，称为单核苷酸多态(SNPs)，已被证明会改变受伤和感染后的临床结果。在X染色体连锁SNPs的案例中，男性和女性是不同的，因为女性携带父母的两条X染色体并显示出细胞X染色体嵌合体，而男性只携带一条X染色体。这些研究将检验这一新的假设，即X连锁基因突变的细胞嵌合体在感染的免疫反应期间可以使宿主受益。更好地了解在脓毒症条件下发挥作用的保护细胞机制可能会导致在治疗危重病方面的先进方案。

DESCRIPTION (provided by applicant): Females as compared to males display better general health status, longer life span and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This project will test the question of whether the presence of cellular mosaicism of X chromosome-linked protein variants in females represents a functionally adaptive cellular system that is advantageous during the host response to infections. Cells from females carry both parental X chromosomes (maternal, Xm and paternal, Xp) whereas males carry only one X chromosome that is derived from the mother (Xm). As the result of dosage compensation and random X inactivation, half of the cells from females express proteins either from Xm or Xp, respectively. Therefore, females are cellular mosaics for X-linked polymorphic proteins. Several genes encoding key regulatory and metabolic proteins involved in the innate immune response reside on the X chromosome. The study focuses on two X-linked proteins, the first, gp91phox (Cybb) is a critical protein component of the NADPH oxidase complex that produces superoxide anion required for bacterial killing; the second, IRAK1 (IL-1 receptor associated kinase-1) is an important component of TLR-mediated cell signaling pathway. The investigations will employ experimental models of endotoxemia and sepsis utilizing mouse strains that carry genetically silenced forms of these X-linked proteins. Changes in blood and bone marrow cell compositions as well as phagocyte infiltration into lung, spleen and liver will be tested following sepsis or endotoxemia. Observations will be compared between mosaics and single-population homo/hemizygous deficient or WT animals. Alterations in cell signaling, cytokine production and redox-dependent cell functions will also be determined and compared. We hypothesize that female mosaics will display acute heterogeneous functional adaptation that will be associated with improved outcome following sepsis or endotoxemia. This will be reflected in skewed cell composition and cell activation toward mosaic subpopulations expressing the advantageous alleles together with improved bacterial killing and survival. The studies will broaden our understanding of the cellular and biochemical mechanisms responsible for immuno-modulation by X- chromosome mosaicism and gender and may open new perspectives in treating the critically ill. PUBLIC HEALTH RELEVANCE: Small differences in the genetic makeup of individuals, called single nucleotide polymorphisms (SNPs), have been shown to alter the clinical outcomes after injury and infection. In the case of X-chromosome-linked SNPs, males and females are different because females carry both parental X-chromosomes and show cellular X-chromosome mosaicism whereas males carry only one X-chromosome. The studies will test the novel hypothesis that cellular mosaicism for X-linked genetic mutations can benefit the host during the immune response to infections. Better understanding of the protecting cellular mechanisms that are in effect during septic conditions could lead to advanced protocols in treating the critically ill.