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的总体健康状况更好，寿命更长，临床病程改善。一般认为，女性的优势与性激素的作用有关。该项目将测试一个问题，即女性中X染色体连锁蛋白变异的细胞嵌合现象是否代表了一种功能适应性细胞系统，在宿主对感染的反应中是有利的。来自雌性的细胞携带两个亲本X染色体（母体，Xm和父亲，Xp），而雄性只携带来自母亲的一条X染色体（Xm）。剂量补偿和随机X失活的结果是，一半的雌性细胞分别表达来自Xm或Xp的蛋白质。因此，女性是x连锁多态性蛋白的细胞嵌合体。编码先天性免疫应答的关键调节和代谢蛋白的几个基因位于X染色体上。该研究主要关注两个x连接蛋白，第一个是gp91phox (Cybb)，它是NADPH氧化酶复合物的关键蛋白组分，产生细菌杀死所需的超氧阴离子；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。研究将采用内毒素血症和败血症的实验模型，利用携带这些x连锁蛋白基因沉默形式的小鼠品系。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、脾和肝脏的浸润。观察结果将比较嵌合体和单种群人/半合子缺陷或WT动物。细胞信号、细胞因子产生和氧化还原依赖性细胞功能的改变也将被确定和比较。我们假设女性嵌合体将显示急性异质功能适应，这将与脓毒症或内毒素血症后的改善结果相关。这将反映在倾斜的细胞组成和细胞向表达有利等位基因的马赛克亚群的激活，以及提高细菌的杀伤和存活率。这些研究将扩大我们对X染色体嵌合和性别对免疫调节的细胞和生化机制的理解，并可能为治疗危重症开辟新的视角。公共卫生相关性：个体基因组成的微小差异，称为单核苷酸多态性（snp），已被证明可以改变损伤和感染后的临床结果。在x染色体连锁snp的情况下，雄性和雌性是不同的，因为雌性携带亲代x染色体并显示细胞x染色体嵌合体，而雄性只携带一条x染色体。这些研究将验证一种新的假设，即x连锁基因突变的细胞嵌合体在对感染的免疫反应中有益于宿主。更好地了解在脓毒性条件下有效的保护细胞机制可能会导致治疗危重病人的先进方案。

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.