Inflammatory Bowel Disease Susceptibility Gene Regulation of Anemia

炎症性肠病易感基因对贫血的调控

基本信息

批准号：
10363673
负责人：
Declan McCole
金额：
$ 19.44万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10363673
关键词：
Anemia Anemia due to Chronic Disorder Autoimmune Biological Models Blood Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complication Conflict (Psychology)Crohn&apos s disease Data Defect Development Diagnosis Drug or chemical Tissue Distribution Duodenal Diseases Duodenum Enterocytes Epithelial Cells Erythrocytes Erythropoiesis Etiology Experimental Models Gene Expression Regulation Genes Genetic Markers Genotype Goals Health Heme Hemoglobin Hemoglobin concentration result Hemorrhage Hepatocyte Homeostasis Hormones Human IL6 gene Impairment In Vitro Inflammatory Inflammatory Bowel Diseases Interleukin-6 Intervention Intestinal Absorption Intestines Iron Iron Overload Iron deficiency anemia Iron-Regulatory Proteins JAK1 gene Knockout Mice Liver Malabsorption Syndromes Measures Mediating Metabolism Molecular Mus Organ Outcome Pathway interactions Patients Phosphoric Monoester Hydrolases Play Population Protein Tyrosine Phosphatase Proteins Proteomics Quality of life Recycling Regulation Risk Role Route STAT3 gene Serum Severity of illness Single Nucleotide Polymorphism Source Susceptibility Gene Testing Toxic effect Translating Ulcerative Colitis absorption cell type cytokine disorder risk genotyped patients hepcidin in vitro Model in vivo indexing inorganic phosphate insight intestinal epithelium iron absorption iron deficiency iron metabolism iron supplementation jejunum loss of function loss of function mutation macrophage novel novel therapeutic intervention patient biomarkers protein expression risk variant uptake virtual

Anemia Anemia due to Chronic Disorder Autoimmune Biological Models Blood Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complication Conflict (Psychology)Crohn&apos s disease Data Defect Development Diagnosis Drug or chemical Tissue Distribution Duodenal Diseases Duodenum Enterocytes Epithelial Cells Erythrocytes Erythropoiesis Etiology Experimental Models Gene Expression Regulation Genes Genetic Markers Genotype Goals Health Heme Hemoglobin Hemoglobin concentration result Hemorrhage Hepatocyte Homeostasis Hormones Human IL6 gene Impairment In Vitro Inflammatory Inflammatory Bowel Diseases Interleukin-6 Intervention Intestinal Absorption Intestines Iron Iron Overload Iron deficiency anemia Iron-Regulatory Proteins JAK1 gene Knockout Mice Liver Malabsorption Syndromes Measures Mediating Metabolism Molecular Mus Organ Outcome Pathway interactions Patients Phosphoric Monoester Hydrolases Play Population Protein Tyrosine Phosphatase Proteins Proteomics Quality of life Recycling Regulation Risk Role Route STAT3 gene Serum Severity of illness Single Nucleotide Polymorphism Source Susceptibility Gene Testing Toxic effect Translating Ulcerative Colitis absorption cell type cytokine disorder risk genotyped patients hepcidin in vitro Model in vivo indexing inorganic phosphate insight intestinal epithelium iron absorption iron deficiency iron metabolism iron supplementation jejunum loss of function loss of function mutation macrophage novel novel therapeutic intervention patient biomarkers protein expression risk variant uptake virtual

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项目摘要

SUMMARY Anemia resulting from iron deficiency is the most frequent extraintestinal manifestation of inflammatory bowel disease (IBD) and can significantly impact patient health and quality of life. However, the mechanisms of iron deficiency associated with IBD are poorly understood. Moreover, the contributions of susceptibility genes associated with increased risk of IBD to the development of anemia are virtually unknown. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) loss-of-function mutations are genetic markers of increased IBD risk. This proposal builds on our novel preliminary data identifying that in a proteomic screen of serum from PTPN2- genotyped IBD patients, altered expression of iron-handling proteins was the #1 pathway modified in IBD patients harboring the rs1893217 PTPN2 loss-of-function risk allele, independent of disease severity. We also show that Ptpn2-deficient mice have anemia. We hypothesize that PTPN2 is a critical regulator of iron handling mechanisms and that loss of PTPN2 activity disrupts iron homeostasis and metabolism. The goal of this study is to translate patient biomarker findings into experimental models to mechanistically explore PTPN2 regulation of iron transport, and understand how PTPN2 loss of function may contribute to iron deficiency in IBD. To dissect the mechanisms by which PTPN2 regulates iron homeostasis, we will focus on PTPN2 regulation of two essential cell types that are critically important for iron homeostasis. Intestinal epithelial cells are responsible for the only entry route for iron into the body: absorption by intestinal epithelial cells, while macrophages are responsible for capturing and recycling iron from the breakdown of erythrocytes. In Aim 1, we will identify the role of PTPN2 in regulating intestinal epithelial iron uptake by measuring iron absorption and exit in vivo and in vitro using enteroids from constitutive and inducible intestinal epithelial-specific Ptpn2 knockout mice. We will also determine how PTPN2 regulates molecular pathways involved in iron transport and metabolism. In Aim 2, we will identify the mechanisms of PTPN2 regulation of macrophage iron handling by determining how PTPN2 deficiency alters iron recycling and regulation of essential iron- handling proteins using macrophage-specific PTPN2 knockout mice and CRISPR-modified human macrophages expressing the clinical PTPN2 loss-of-function rs1893217 risk allele. Expected Outcomes & Impact: These studies will translate findings in PTPN2-genotyped patients to complementary in vivo and in vitro model systems. We will not only generate fundamental and highly novel insights into PTPN2 regulation of iron homeostasis and its potential role as a complicating factor in anemia associated with IBD, but will also identify novel targets for intervention.

概括铁缺乏症引起的贫血是最常见的肠外表现炎症性肠病（IBD），可以显着影响患者的健康和生活质量。但是，与IBD相关的铁缺乏的机制知之甚少。此外，与IBD风险增加有关的易感基因的贡献贫血的发展实际上是未知的。蛋白质酪氨酸磷酸酶非受体2型（PTPN2）功能丧失突变是IBD风险增加的遗传标记。这个建议建立在我们新颖的初步数据的基础上，确定在PTPN2-血清的蛋白质组学筛选中基因分型IBD患者，铁处理蛋白的表达改变是修改的＃1途径在具有RS1893217 PTPN2功能丧失风险等位基因的IBD患者中疾病的严重程度。我们还表明PTPN2缺陷小鼠患有贫血。我们假设这一点 PTPN2是铁处理机制的关键调节因子，PTPN2活性的丧失破坏了铁稳态和代谢。这项研究的目的是翻译患者生物标志物在实验模型中的发现，以机械学探索铁转运的PTPN2调节，并了解PTPN2功能的损失可能导致IBD的铁缺乏症。剖析 PTPN2调节铁稳态的机制，我们将重点放在PTPN2调节上在两种对铁稳态至关重要的基本细胞类型中。肠上皮细胞是铁进入体内唯一的进入途径：肠吸收上皮细胞，而巨噬细胞负责捕获和回收铁红细胞的分解。在AIM 1中，我们将确定PTPN2在调节肠道中的作用通过在体内和体外测量铁的吸收和出口，使用肠tod脚来测量上皮铁的吸收从本构和可诱导的肠上皮特异性PTPN2基因敲除小鼠。我们也会确定PTPN2如何调节参与铁运输和代谢的分子途径。在AIM 2中，我们将确定巨噬细胞处理PTPN2调节的机制通过确定PTPN2缺乏症如何改变铁回收利用和基本铁的调节使用巨噬细胞特异性PTPN2敲除小鼠处理蛋白质和CRISPR修饰表达临床PTPN2功能丧失RS1893217风险等位基因的人类巨噬细胞。预期结果和影响：这些研究将转化为PTPN2制定的发现患者互补体内和体外模型系统。我们不仅会生成对铁稳态调节PTPN2调节及其潜力的基本和高度新颖的见解作为与IBD相关的贫血的复杂因素的作用，但也将确定新的目标干涉。