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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

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.

总结缺铁引起的贫血是最常见的肠外表现，炎症性肠病（IBD），并可显着影响患者的健康和生活质量。然而，与IBD相关的铁缺乏的机制知之甚少。此外，与IBD风险增加相关的易感基因对IBD易感性的贡献，贫血的发展几乎是未知的。蛋白酪氨酸磷酸酶非受体2型（PTPN 2）功能丧失突变是IBD风险增加的遗传标记。这项建议建立在我们的新的初步数据，确定在蛋白质组筛选的血清从PTPN 2- 对IBD患者进行基因分型，铁处理蛋白表达的改变是1号途径的改变，在携带rs 1893217 PTPN 2功能丧失风险等位基因的IBD患者中，疾病严重程度。我们还表明，Ptpn 2缺陷型小鼠有贫血。我们假设 PTPN 2是铁处理机制的关键调节剂，并且PTPN 2活性的丧失破坏了铁处理机制。铁稳态和代谢。本研究的目的是将患者的生物标志物将发现转化为实验模型以机械地探索PTPN 2对铁转运的调节，并了解PTPN 2功能丧失如何导致IBD缺铁。解剖 PTPN 2调节铁稳态的机制，我们将集中讨论PTPN 2的调节作用这两种细胞对铁的体内平衡至关重要。肠上皮细胞负责铁进入体内的唯一途径：肠道吸收上皮细胞，而巨噬细胞负责捕获和回收铁，红细胞的分解。在目标1中，我们将确定PTPN 2在调节肠上皮细胞中的作用。上皮铁摄取--用类肠上皮测量体内和体外铁吸收和排出来自组成型和诱导型肠上皮特异性Ptpn 2敲除小鼠。我们还将确定PTPN 2如何调节参与铁转运和代谢的分子途径。在目标2中，我们将确定PTPN 2调节巨噬细胞铁处理的机制，通过确定PTPN 2缺乏如何改变铁的再循环和必需铁的调节，使用巨噬细胞特异性PTPN 2敲除小鼠和CRISPR修饰的表达临床PTPN 2功能丧失rs 1893217风险等位基因的人巨噬细胞。预期结果和影响：这些研究将转化PTPN 2基因分型的结果患者补充体内和体外模型系统。我们不仅会产生对PTPN 2调节铁稳态及其潜力的基本和高度新颖的见解作为IBD相关贫血的复杂因素，但也将确定新的靶点，干预