X chromosome, injury and infection

X染色体、损伤和感染

• 批准号: 8241156
• 负责人: ZOLTAN SPOLARICS
• 金额: $ 28.59万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241156
• 关键词: Acute; Address; Alleles; Animals; Apoptotic; Biochemical; Blood; Bone Marrow; Bone Marrow Cells; Cell physiology; Cells; Clinical; Complex; Critical Illness; Cytokine Signaling; Defense Mechanisms; Dosage Compensation (Genetics); Endotoxemia; Enzyme-Linked Immunosorbent Assay; Experimental Models; Female; Flow Cytometry; Gender; Gene Mutation; Gene Targeting; Genes; Genetic; Gonadal Steroid Hormones; Health; Health Status; Histology; Homo; Human; Immune; Immune response; In Vitro; Individual; Infection; Infiltration; Inflammation; Injury; Interleukin-1; Investigation; Lead; Ligation; Link; Liver; Longevity; Lung; MAPK8 gene; Measures; Mediating; Metabolic; Mosaicism; Mothers; Mouse Strains; Mus; NADPH Oxidase; Organ; Outcome; Oxidation-Reduction; Phagocytes; Phenotype; Phosphotransferases; Play; Population; Production; Proteins; Protocols documentation; Puncture procedure; Respiratory Burst; Role; Sepsis; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Spleen; Superoxides; System; Testing; Variant; X Chromosome; X Inactivation; bactericide; base; cytokine; dimorphism; immune function; improved; in vivo; killings; link protein; male; member; novel; receptor; response; septic

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.

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、更长的寿命和改善的临床病程。一般认为，女性的优势与性激素的作用有关。该项目将测试的问题，是否存在的X染色体连锁蛋白变异体的细胞镶嵌在女性代表一个功能适应性细胞系统，这是有利的宿主对感染的反应。来自雌性的细胞携带双亲X染色体（母本Xm和父本Xp），而雄性细胞仅携带一条来自母亲的X染色体（Xm）。作为剂量补偿和随机X失活的结果，来自雌性的一半细胞分别表达来自Xm或Xp的蛋白质。因此，女性是X连锁多态性蛋白的细胞镶嵌体。编码参与先天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。该研究主要集中在两个X连锁蛋白，第一，gp 91 phox（Cybb）是NADPH氧化酶复合物的关键蛋白组分，产生细菌杀伤所需的超氧阴离子;第二，IRAK 1（IL-1受体相关激酶-1）是TLR介导的细胞信号通路的重要组分。研究将采用内毒素血症和败血症的实验模型，这些模型使用携带这些X-连锁蛋白质的遗传沉默形式的小鼠品系。败血症或内毒素血症后，将检测血液和骨髓细胞组成的变化以及吞噬细胞浸润至肺、脾和肝的情况。将比较嵌合体和单一群体同源/半合子缺陷或WT动物之间的观察结果。还将确定和比较细胞信号传导、细胞因子产生和氧化还原依赖性细胞功能的改变。我们假设女性嵌合体将表现出急性异质性功能适应，这将与改善脓毒症或内毒素血症后的结局相关。这将反映在偏向表达有利等位基因的嵌合亚群的细胞组成和细胞活化以及改善的细菌杀伤和存活。这些研究将拓宽我们对X染色体嵌合体和性别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。公共卫生关系：个体遗传组成的微小差异，称为单核苷酸多态性（SNP），已被证明会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，男性和女性是不同的，因为女性携带两个亲本X染色体并显示细胞X染色体嵌合体，而男性仅携带一个X染色体。这些研究将测试新的假设，即X连锁基因突变的细胞嵌合体可以在对感染的免疫反应中使宿主受益。更好地理解在脓毒症条件下有效的保护细胞机制可能会导致治疗危重病的先进方案。

项目成果

Female X-chromosome mosaicism for gp91phox expression diversifies leukocyte responses during endotoxemia.

• DOI: 10.1097/ccm.0b013e3181eb9ed6
• 发表时间: 2010-10
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Chandra R;Federici S;Haskó G;Deitch EA;Spolarics Z
• 通讯作者: Spolarics Z

In gender-based outcomes, sex hormones may be important but it is in the genes*.

在基于性别的结果中，性激素可能很重要，但它存在于基因中*。

• DOI: 10.1097/ccm.0000000000000268
• 发表时间: 2014
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Spolarics,Zoltán

IRAK1-dependent signaling mediates mortality in polymicrobial sepsis.

• DOI: 10.1007/s10753-013-9692-1
• 发表时间: 2013-12
• 期刊: INFLAMMATION
• 影响因子: 5.1
• 作者: Chandra, Rachna;Federici, Stephanie;Bishwas, Tripti;Nemeth, Zoltan H.;Deitch, Edwin A.;Thomas, James A.;Spolarics, Zoltan
• 通讯作者: Spolarics, Zoltan