A novel role for Reelin therapeutics in inflammatory bowel disease

Reelin 疗法在炎症性肠病中的新作用

• 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
• 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' 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

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.

摘要 导致炎症性肠病（IBD）发病的因素仍然不完全 明白虽然特定的遗传因素可能会增加风险，但大多数IBD并不容易发生。 根据遗传学解释。肠道微生物组的生态失调也有牵连。 一旦IBD建立，慢性炎症是一个中心标志，也是IBD治疗的主要靶点。 疗法IBD的两种形式，克罗恩病（CD）和溃疡性结肠炎（UC），通常是 以缓解期和爆发期为特点。耀斑可能是严重的，很难 逆转，造成不可逆的组织损伤。IBD的现有疗法不足 并且识别新的目标是一个重要的目标。我们发现了一个新的系统 来控制炎症Reelin是一种血浆蛋白，与内皮细胞ApoER 2结合， 增加参与炎性转运的多种内皮细胞受体的表达 细胞进入炎症区域。这项提议的主要目的是检验我们的假设， 靶向Reelin/ApoER 2系统在治疗上可能对IBD有效。初步 研究，我们已经表明，我们可以消耗血浆中的Reelin在一个稳定的方式使用抗- Reelin单克隆抗体。我们也有可用的小鼠，其中Reelin被删除。在 具体目标1，我们将检验Reelin缺失将降低结肠炎严重程度的假设 葡聚糖硫酸钠（DSS）的反应。在目标2中，我们将测试 抗Reelin抗体在减弱对DSS的应答方面的作用。这些证明原理的实验 将提供临床前证据，支持我们靶向Reelin/ApoER 2系统的目标 治疗IBD患者的临床试验。