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）是一种高度普遍的肠道疾病，目前尚无治愈方法。 当前治疗的抗TNF疗法完成，可减轻症状，但并不针对 疾病的原因。在IBD中已经鉴定出了X连锁凋亡蛋白（XIAP）的突变 患者，表明XIAP活性降低会导致IBD。 IBD中的特征表现之一是 过度死亡和对肠上皮的损害，导致肠炎，因为 针对腔菌群的肠上皮屏障受损。我们建议针对根本原因 通过将XIAP活性直接恢复到IBD患者的体内稳态水平，IBD的脑海中。 XIAP是最有力的 胱天蛋白酶和凋亡的抑制剂。减少的XIAP与炎性体的激活增加有关 先天免疫宿主防御和炎症性肿瘤坏死因子（TNF）和 白介素（IL）-1b细胞因子，导致高炎症，这也是IBD的特征。我们预测 恢复XIAP在IBD中的正常活性将控制肠上皮的过量细胞死亡 细胞并恢复肠上皮的健康功能和稳态周转。我们的研究 这里的建议将利用促凋亡蛋白艺术，该蛋白质对XIAP进行负调节并促进其 泛素蛋白酶体系统降解。我们假设艺术是重要的 IBD的治疗靶标通过将XIAP的降低活性恢复到正常状态，从而进行治疗靶标。与Murine和 人类结肠器官，我们将测试以下想法：XIAP在具有IBD相关的细胞中的活性降低 可以通过抑制艺术来克服突变。由于响应压力而诱导艺术的表达 和DNA损害，这也可能解释没有XIAP突变的IBD患者的XIAP活性降低。那， 提高XIAP活动的策略可能超出实施XIAP突变的案例的广泛影响 在IBD中。利用完整的方法，我们将使用专有的艺术和XIAP的活动调节 我们已经确定的小型分子“艺术抗逆转击犬”和“ Xiap-aghists”的小组。我们试图提供 概念证明我们的“艺术抗议者”和“ XIAP-aghists”将能够恢复正常的XIAP 与IBD相关的XIAP突变作为IBD的新型治疗策略中的功能。我们还将测试 这些小分子在IBD的动物模型中。我们有两个具体的目标：（1）确定艺术的作用 在调节IBD中XIAP诱导的细胞凋亡和炎症时，（2）确定最有效的艺术抗逆转录病毒师 和XIAP激动剂的小分子，可在IBD模型中恢复XIAP的表达和功能。我们的建议 提供了一种由自然对手艺术来确定XIAP的根本新方法，该方法的疗法 尚未调查剥削。我们的长期目标是化合物的临床开发 反向肠上皮损害并促进粘膜愈合，以实现有效而持久 治疗IBD。