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.

抽象的 导致炎症性肠病（IBD）发病的因素仍然不完全 明白了。尽管特定的遗传因素可能会增加风险，但大多数 IBD 并不容易 根据遗传学解释。肠道微生物群的菌群失调也与此有关。 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。 治疗。克罗恩病 (CD) 和溃疡性结肠炎 (UC) 这两种形式的 IBD 通常都是 其特点是缓解期和耀斑期。耀斑可能很严重且难以处理 逆转，导致不可逆转的组织损伤。现有的 IBD 疗法还不够 确定新目标是一个重要目标。我们已经确定了一个新颖的系统 控制炎症。 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 细胞进入炎症区域。该提案的主要目标是检验我们的假设 靶向 Reelin/ApoER2 系统治疗可能对 IBD 有效。在初步 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 Reelin 单克隆抗体。我们还有删除了 Reelin 的小鼠。在 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 是对葡聚糖硫酸钠 (DSS) 做出反应而产生的。在目标 2 中，我们将测试以下效果： 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。