Causes and consequences of neutrophil dysfunction in early onset Crohn's disease

早发型克罗恩病中性粒细胞功能障碍的原因和后果

• 批准号: 9116212
• 负责人: LEE ARMISTEAD DENSON
• 金额: $ 63.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116212
• 关键词: Accounting; Adhesions; Adult; Affect; Age; Age of Onset; Animal Model; Antibodies; Behavior; Bioinformatics; Blood specimen; CSF2RB gene; CYBA gene; Chemotaxis; Child; Childhood; Chronic; Clinical; Code; Complex; Crohn' s disease; DNA; DNA Sequence Alteration; Databases; Development; Diagnosis; Disease; Enrollment; Exhibits; Frequencies; Functional disorder; Gene Mutation; Genes; Genetic; Genomics; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Heritability; High-Throughput Nucleotide Sequencing; Host Defense; ITGAM gene; Immune; Inborn Genetic Diseases; Individual; Inflammatory disease of the intestine; Injury; Intestines; Left; Life; Modeling; Mutation; NADPH Oxidase; North America; Outcome; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Play; Population; Reporting; Respiratory Burst; Role; Serum; Signal Transduction; Single Nucleotide Polymorphism; Stat5 protein; Testing; Time; Variant; age related; antimicrobial; base; biobank; cohort; design; early onset; exome sequencing; experience; gene discovery; genetic variant; genome wide association study; innovation; killings; loss of function; loss of function mutation; microbial; neutrophil; novel; novel therapeutic intervention; novel therapeutics; patient population; patient subsets; peripheral blood; prospective; protein expression; rare variant; response

DESCRIPTION (provided by applicant): Anti-microbial sero-reactivity (AMS) and chronic intestinal inflammation similar to Crohn's Disease (CD) during the first decade of life in children with inherited disorders of phagocyte function suggests that loss-of-function in neutrophil antimicrobial pathways is likely to be a fundamental mechanism of pediatric CD pathogenesis. GWAS in CD have accounted for only a portion of the heritability and have rarely identified few loci of large effect. Rare variants, which GWAS are underpowered to detect, have been hypothesized to explain a substantial fraction of complex disorders like CD, so gene discovery efforts have now shifted to characterization of deleterious / loss of function mutations. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is required for priming of neutrophil antimicrobial function, and bioinformatic analysis of genomic studies has suggested a central role in CD pathogenesis. We discovered that older pediatric (early onset, EO, age 10-17) and adult patients exhibit an acquired basis for neutrophil dysfunction, GM-CSF auto-antibodies (GM-CSF Ab), which increase in titer with increasing age. GM-CSF Ab carriage is associated with reduced neutrophil STAT5 activation, phagocytic capacity, and bacterial killing, and high rates of AMS and stricturing behavior. To test the significance of these exciting developments, we have established a prospective clinical database and biobank for 1130 pediatric CD patients enrolled at diagnosis (the RISK study). We found that neutrophil phagocytosis and bacterial killing is reduced in a subset of patients. VEO patients have exhibited rare coding region mutations in genes predicted to affect GM-CSF priming of bacterial killing (CSF2RB & ITGAM/CD11b) and neutrophil oxidative burst (CYBA/p22phox), while EO patients have exhibited increasing titers of GM-CSF Ab. We hypothesize that genetic variants and GM-CSF Ab cause neutrophil dysfunction and thereby contribute to disease pathogenesis in an age-dependent manner in pediatric CD. Aim 1: Identify all coding genetic mutations in 127 genes likely to disrupt GM-CSF signaling and/or neutrophil function in 500 very early onset pediatric CD patients. Aim 2: Test the functional consequences of genetic mutations upon neutrophil GM-CSF signaling and bacterial killing. Peripheral blood samples will be collected from RISK patients carrying genetic mutations predicted to affect GM-CSF priming and neutrophil function including neutrophil candidate protein expression/localization, GM- CSF signaling, CD64 activation, adhesion, chemotaxis, oxidative burst, phagocytosis, and bacterial killing. We will use state-of-the-art genomic and immune approaches to define for the first time the causes and consequences of neutrophil dysfunction in the largest pediatric CD inception cohort in North America. Collectively, our studies will have direct implications for novel therapeutic approaches designed to modulate this critical host defense pathway in patients who experience the worst outcomes with current approaches.

描述（由申请人提供）：儿童10岁前的抗微生物血清反应性（AMS）和类似克罗恩病（CD）的慢性肠道炎症