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.

概括缺铁引起的贫血是最常见的肠外表现炎症性肠病（IBD），可显着影响患者的健康和生活质量。然而，与 IBD 相关的缺铁机制尚不清楚。此外，易感基因与 IBD 风险增加相关贫血的发生几乎是未知的。蛋白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。这个提议建立在我们新的初步数据的基础上，在对 PTPN2- 血清进行蛋白质组学筛选时确定了这一点对 IBD 患者进行基因分型，铁处理蛋白表达的改变是第 1 条途径的修改在携带 rs1893217 PTPN2 功能丧失风险等位基因的 IBD 患者中，独立于疾病的严重程度。我们还发现 Ptpn2 缺陷的小鼠患有贫血。我们假设 PTPN2 是铁处理机制的关键调节因子，PTPN2 活性的丧失会扰乱铁稳态和新陈代谢。本研究的目标是将患者生物标志物转化为研究结果进入实验模型，以机械方式探索 PTPN2 对铁转运的调节，并了解 PTPN2 功能丧失如何导致 IBD 缺铁。剖析 PTPN2调节铁稳态的机制，我们将重点关注PTPN2的调节两种对铁稳态至关重要的基本细胞类型。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 PTPN2 在调节肠道中的作用通过使用肠类在体内和体外测量铁的吸收和排出来测量上皮铁的吸收来自组成型和诱导型肠上皮特异性 Ptpn2 敲除小鼠。我们也会确定 PTPN2 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 PTPN2 调节巨噬细胞铁处理的机制通过确定 PTPN2 缺乏如何改变铁的循环和必需铁的调节使用巨噬细胞特异性 PTPN2 敲除小鼠和 CRISPR 修饰处理蛋白质表达临床 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 基因分型的研究结果患者补充体内和体外模型系统。我们不仅会产生对 PTPN2 铁稳态调节及其潜力的基本且高度新颖的见解作为 IBD 相关贫血的复杂因素，但也将确定新的靶标干涉。