Modulating XIAP for the Treatment of Inflammatory Bowel Disease

调节 XIAP 治疗炎症性肠病

基本信息

批准号：
10727185
负责人：
Julie Magarian Blander
金额：
$ 22.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727185
关键词：
ART protein Affect Agonist Alleles Animal Model Anti-Tumor Necrosis Factor Therapy Apoptosis Back Binding Caspase Inhibitor Cell Death Cell Death Induction Cell Line Cells Cessation of life Characteristics Chronic Chronic Disease Cicatrix Clinical Colon Crohn&apos s disease Cytoprotection DNA Damage Data Disease Disease model Down-Regulation Epigenetic Process Epithelial Cells Exhibits Food Foundations Gastrointestinal tract structure Genes Genetic Goals Hematopoietic System Host Defense Human Impairment Incidence Induction of Apoptosis Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Injury Interleukins Intestinal Cancer Intestinal Diseases Intestines Knockout Mice Lead Methylation Molecular Mucous Membrane Mus Mutation Natural regeneration Organ Organoids Output Patients Phenotype Physiological Prevalence Prevention Proteins RNA Splicing Relapse Resistance Risk Role Stress System TNF gene TP53 gene Testing Therapeutic Transcriptional Activation Tumor Suppressor Proteins Ubiquitin Ulcerative Colitis Up-Regulation Variant Work antagonist clinical development commensal microbes cytokine gastrointestinal system gut inflammation healing high throughput screening innate immune pathways intestinal epithelium microbiota mouse model multicatalytic endopeptidase complex mutant novel novel strategies prevent pro-apoptotic protein promoter protein expression protein function reduce symptoms response small molecule symptom treatment therapeutic target treatment strategy tumor ubiquitin-protein ligase x-linked inhibitor of apoptosis protein

项目摘要

PROPOSAL SUMMARY Inflammatory bowel disease (IBD) is a highly prevalent intestinal disorder for which there is currently no cure. The current treatment is comprised of anti-TNF therapy which alleviates the symptoms but does not target the cause of the disease. Mutations in the X-linked Inhibitor of apoptosis protein (XIAP) have been identified in IBD patients, suggesting that reduced XIAP activity causes IBD. One of the characteristic manifestations in IBD is excessive death and damage to the intestinal epithelium, which contributes to intestinal inflammation because of the compromised intestinal epithelial barrier against luminal microbiota. We propose to target the root cause of IBD by directly restoring XIAP activity to homeostatic levels in patients with IBD. XIAP is the most potent inhibitor of caspases and apoptosis. Reduced XIAP is associated with increased activation of the inflammasome pathway of innate immune host defense and the upregulation of inflammatory tumor necrosis factor (TNF) and interleukin (IL)-1b cytokines, resulting in hyperinflammation, which is also a characteristic of IBD. We predict that regaining the normal activity of XIAP in IBD would control the excessive cell death of intestinal epithelial cells and restore the healthy function and homeostatic turnover of the intestinal epithelium. The studies we propose here will exploit the pro-apoptotic protein ARTS, which negatively regulates XIAP and promotes its degradation by the Ubiquitin-Proteasome System. We hypothesize that ARTS serves as an important therapeutic target for IBD by boosting the reduced activity of XIAP back to normal. Working with murine and human colonic organoids, we will test the idea that reduced activity of XIAP in cells harboring IBD-associated mutations can be overcome by inhibition of ARTS. Since expression of ARTS is induced in response to stress and DNA-damage, this may also account for reduced XIAP activity in IBD patients without XIAP mutations. Thus, strategies to raise XIAP activity may have broad impact beyond cases in which XIAP mutations are implicated in IBD. Utilizing a complementary approach, we will modulate the activities of ARTS and XIAP using a proprietary panel of small-molecule “ARTS-antagonists” and “XIAP-agonists” which we have identified. We seek to provide proof-of-concept that our “ARTS-antagonists” and “XIAP-agonists” will be able to restore to normal the XIAP function in cells with IBD-associated XIAP mutations as a novel treatment strategy for IBD. We will also test these small molecules in an animal model of IBD. We have two specific aims: (1) Determine the role of ARTS in regulating XIAP-induced apoptosis and inflammation in IBD, and (2) Identify the most potent ARTS-antagonist and XIAP-agonist small molecules that restore XIAP expression and function in IBD models. Our proposal provides a radical new approach for regulating XIAP by its natural antagonist ARTS, whose therapeutic exploitation has not yet been investigated. Our long-term goal is the clinical development of compounds that reverse damage to the intestinal epithelium and promote mucosal healing for an effective and long-lasting treatment of IBD.

提案摘要炎症性肠病（IBD）是一种非常普遍的肠道疾病，目前尚无法治愈。目前的治疗包括抗 TNF 疗法，该疗法可减轻症状，但不针对 IBD 的 X 连锁凋亡抑制蛋白 (XIAP) 突变已被确定。患者，表明 XIAP 活性降低会导致 IBD。过度死亡和肠上皮损伤，导致肠道炎症，因为我们建议针对肠内微生物群受损的肠上皮屏障的根本原因。通过直接将 IBD 患者的 XIAP 活性恢复至稳态水平来治疗 IBD。半胱天冬酶和细胞凋亡的抑制剂。 XIAP 减少与炎症小体激活增加有关。先天免疫宿主防御途径和炎性肿瘤坏死因子（TNF）的上调白细胞介素 (IL)-1b 细胞因子，导致过度炎症，这也是我们预测的 IBD 的一个特征。恢复IBD中XIAP的正常活性将控制肠上皮细胞的过度死亡细胞并恢复肠上皮的健康功能和稳态更新。这里提出将利用促凋亡蛋白 ARTS，它对 XIAP 进行负调节并促进其我们勇敢地说，ARTS 是一种重要的降解方法。通过将降低的 XIAP 活性恢复到正常水平来实现 IBD 的治疗目标。人类结肠类器官，我们将测试这样的想法，即 IBD 相关细胞中 XIAP 的活性降低突变可以通过抑制 ARTS 来克服，因为 ARTS 的表达是响应应激而诱导的。和 DNA 损伤，这也可能是没有 XIAP 突变的 IBD 患者 XIAP 活性降低的原因。提高 XIAP 活性的策略可能会产生广泛的影响，超出涉及 XIAP 突变的情况在 IBD 中，我们将使用专有的方法来调节 ARTS 和 XIAP 的活动。我们寻求提供小分子“ARTS 拮抗剂”和“XIAP 激动剂”组。概念验证我们的“ARTS 拮抗剂”和“XIAP 激动剂”将能够使 XIAP 恢复正常我们还将测试 IBD 相关 XIAP 突变细胞中的功能作为 IBD 的新治疗策略。这些小分子在 IBD 动物模型中的作用我们有两个具体目标：（1）确定 ARTS 的作用。调节 IBD 中 XIAP 诱导的细胞凋亡和炎症，以及 (2) 鉴定最有效的 ARTS 拮抗剂我们的建议是恢复 IBD 模型中 XIAP 表达和功能的 XIAP 激动剂小分子。提供了一种通过其天然拮抗剂 ARTS 调节 XIAP 的全新方法，其治疗我们的长期目标是临床开发化合物。逆转肠上皮损伤，促进粘膜愈合，达到有效、持久的效果治疗炎症性肠病。