Modulating XIAP for the Treatment of Inflammatory Bowel Disease

调节 XIAP 治疗炎症性肠病

• 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
• 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' 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

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 疾病的原因。 X 连锁凋亡抑制剂 (XIAP) 的突变已在 IBD 中被发现 患者，表明 XIAP 活性降低会导致 IBD。 IBD 的特征性表现之一是 过度死亡和肠上皮损伤，导致肠道炎症，因为 肠上皮屏障对管腔微生物群的损害。我们建议针对根本原因 通过直接将 IBD 患者的 XIAP 活性恢复至稳态水平来治疗 IBD。 XIAP是最强大的 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相关 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 IBD 的一个特征。我们预测 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。我们的研究 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 泛素-蛋白酶体系统降解。我们假设 ARTS 是一个重要的 通过促进降低的 XIAP 活性恢复正常来实现 IBD 的治疗目标。与小鼠一起工作 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。由于 ARTS 的表达是响应压力而诱导的 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。因此， 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 在炎症性肠病中。利用互补的方法，我们将使用专有的技术来调节 ARTS 和 XIAP 的活动 我们已经确定了小分子“ARTS 拮抗剂”和“XIAP 激动剂”组。我们力求提供 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 在具有 IBD 相关 XIAP 突变的细胞中发挥作用，作为 IBD 的一种新治疗策略。我们也会测试 IBD 动物模型中的这些小分子。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 和 XIAP 激动剂小分子，可恢复 IBD 模型中的 XIAP 表达和功能。我们的建议 提供了一种通过其天然拮抗剂 ARTS 调节 X​​IAP 的全新方法，其治疗 尚未对利用情况进行调查。我们的长期目标是临床开发能够 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。