A novel role for Reelin therapeutics in inflammatory bowel disease

Reelin 疗法在炎症性肠病中的新作用

基本信息

批准号：
10079713
负责人：
STEVEN L. GONIAS
金额：
$ 40万
依托单位：
REELIN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079713
关键词：
Aminosalicylate Anti-Inflammatory Agents Antibodies Apolipoproteins Attenuated Autopsy Binding Binding Proteins Biological Biological Models Biological Products Blood Body Weight decreased Cells Chronic Cicatrix Clinical Trials Colitis Colon Crohn&apos s disease Degenerative Disorder Disease Progression Disease model Disease remission Drug Targeting E-Selectin Endothelial Cells Excision Extracellular Matrix Proteins Extravasation Feces Flare Flow Cytometry Genes Genetic Goals Histologic Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Infiltrate Integrins Intercellular adhesion molecule 1 Intestines Janus kinase Laboratories Length Leukocyte Adhesion Molecules Measures Medical Methotrexate Modeling Molecular Monitor Monoclonal Antibodies Mus Mutation Operative Surgical Procedures Pathology Patients Pattern Penetrance Pharmaceutical Preparations Plasma Plasma Proteins Predisposition Receptor Cell Relapse Risk Role Severities Severity of illness Signal Transduction Site Sodium Dextran Sulfate System TNF gene Testing Therapeutic Tissues Ulcerative Colitis United States Vascular Cell Adhesion Molecule-1 apolipoprotein E receptor 2 base chronic ulcer cytokine drinking water dysbiosis efficacy testing experience experimental study gut microbiome human model inhibiting antibody intestinal epithelium intestinal injury mouse model mucosal addressin cell adhesion molecule-1 neutralizing antibody novel novel therapeutics pre-clinical prevent receptor recruit response targeted agent targeted treatment trafficking

项目摘要

Abstract Factors that contribute to the onset of inflammatory bowel disease (IBD) remain incompletely understood. Although specific genetic factors may increase risk, most IBD cannot be readily explained based on genetics. Dysbiosis in intestinal microbiomes also has been implicated. Once IBD is established, chronic inflammation is a central hallmark and also a major target for therapy. Both forms of IBD, Crohn’s Disease (CD) and Ulcerative Colitis (UC), are typically characterized by periods of remission and flares. The flares can be serious and difficult to reverse, contributing to irreversible tissue damage. Existing therapies for IBD are insufficient and identification of new targets represents an important goal. We have identified a novel system that controls inflammation. Reelin, a plasma protein, binds to endothelial cell ApoER2, increasing expression of diverse endothelial cell receptors involved in transporting inflammatory cells into regions of inflammation. The major goal of this proposal is to test our hypothesis that targeting the Reelin/ApoER2 system therapeutically may be efficacious in IBD. In preliminary studies, we have shown that we can deplete the plasma of Reelin in a stable manner using anti- Reelin monoclonal antibodies. We also have available mice in which Reelin is deleted. In Specific Aim 1, we will test the hypothesis that Reelin deletion will decrease the severity of colitis that develops in response to dextran sodium sulfate (DSS). In Aim 2, we will test the efficacy of anti-Reelin antibody at attenuating the response to DSS. These proof of principle experiments will provide pre-clinical evidence in support of our goal to target the Reelin/ApoER2 system therapeutically in clinical trials in IBD patients.

抽象的导致炎症性肠病（IBD）发病的因素仍然不完全虽然特定的遗传因素可能会增加风险，但大多数 IBD 并不容易被理解。基于遗传学的解释也与肠道微生物群的失调有关。一旦 IBD 形成，慢性炎症就是一个核心标志，也是治疗的主要目标。克罗恩病 (CD) 和溃疡性结肠炎 (UC) 这两种形式的 IBD 都是典型的治疗方法。其特点是有缓解期和发作期，发作可能很严重且难以治疗。导致不可逆的组织损伤，现有的 IBD 疗法是不够的。新目标的确定是我们确定的一个重要目标。控制炎症的 Reelin 是一种血浆蛋白，与内皮细胞 ApoER2 结合，增加参与炎症转运的多种内皮细胞受体的表达该提案的主要目标是检验我们的假设：初步认为，靶向 Reelin/ApoER2 系统对 IBD 可能有效。研究表明，我们可以使用抗-抗体以稳定的方式耗尽 Reelin 的血浆我们还提供了 Reelin 缺失的小鼠。具体目标 1，我们将检验 Reelin 缺失会降低结肠炎严重程度的假设在目标 2 中，我们将测试其功效。抗 Reelin 抗体可减弱对 DSS 的反应，这些原理实验证明。将提供临床前证据支持我们针对 Reelin/ApoER2 系统的目标 IBD 患者的临床试验中具有治疗作用。