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.

建议书摘要 炎症性肠病(IBD)是一种高度流行的肠道疾病，目前尚无治愈方法。 目前的治疗包括抗肿瘤坏死因子治疗，这种治疗可以缓解症状，但不针对 疾病的起因。已在IBD中发现X连锁的凋亡抑制蛋白(XIAP)突变 这表明XIAP活动减少导致IBD。炎症性肠病的特征之一是 过多的死亡和对肠道上皮的损害，这会导致肠道炎症，因为 对肠腔微生物群的肠道上皮屏障的破坏。我们建议针对根本原因 通过直接将IBD患者的XIAP活性恢复到动态平衡水平来治疗IBD。XIAP是最强大的 半胱氨酸氨基转移酶抑制物与细胞凋亡。XIAP降低与炎性小体的激活增加有关 天然免疫宿主防御途径与炎性肿瘤坏死因子和 白介素1b细胞因子，导致高度炎症，这也是IBD的特征。我们预测 IBD时XIAP恢复正常活性可控制肠上皮细胞过度死亡 从而恢复肠道上皮的健康功能和动态平衡。我们的研究 建议在这里利用促凋亡蛋白ARTS，它负向调节XIAP并促进其 泛素-蛋白酶体系统的降解。我们假设艺术是一种重要的 通过促进降低的XIAP活性恢复正常来治疗IBD。与小鼠和 人类结肠有机化合物，我们将测试在携带IBD相关疾病的细胞中XIAP活性降低的想法 基因突变可以通过抑制ARTS来克服。由于ARTS的表达是在应激反应中诱导的 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活性的策略可能会在涉及XIAP突变的病例之外产生广泛影响 在IBD。利用互补的方法，我们将使用专有的 我们已经确定的小分子“ARTS-拮抗剂”和“XIAP-激动剂”小组。我们寻求提供 证明我们的“艺术拮抗剂”和“XIAP激动剂”将能够使XIAP恢复正常 IBD相关XIAP突变细胞的功能作为治疗IBD的新策略。我们还将测试 这些小分子在IBD的动物模型中。我们有两个具体目标：(1)确定艺术的作用 在调节XIAP诱导的IBD细胞凋亡和炎症中的作用，以及(2)确定最有效的ARTS拮抗剂 以及在IBD模型中恢复XIAP表达和功能的XIAP激动剂小分子。我们的建议 为通过其天然拮抗剂ARTS调节XIAP提供了一种激进的新途径，其治疗作用 剥削还没有被调查。我们的长期目标是化合物的临床开发 逆转对肠上皮的损伤，促进粘膜愈合，有效而持久 IBD的治疗。