Modulating XIAP for the Treatment of Inflammatory Bowel Disease

提案摘要 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TNF治疗，其减轻症状，但不靶向治疗。 疾病的原因。X连锁凋亡抑制蛋白（XIAP）的突变已在IBD中被鉴定 患者，表明XIAP活性降低导致IBD。IBD的特征性表现之一是 过度死亡和肠上皮细胞损伤，这有助于肠道炎症， 受损的肠上皮屏障对抗管腔微生物群。我们建议针对根本原因 通过直接将XIAP活性恢复到IBD患者体内的稳态水平来治疗IBD。XIAP是最有效的 半胱天冬酶抑制剂和细胞凋亡。XIAP的减少与炎性小体的激活增加有关 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IBD的特征。我们预测 IBD时恢复XIAP的正常活性将控制肠上皮细胞的过度死亡 细胞和恢复健康的功能和肠上皮细胞的稳态周转。我们的研究 本文提出将利用促凋亡蛋白ARTS，其负调节XIAP并促进其表达。 通过泛素-蛋白酶体系统降解。我们假设，艺术作为一个重要的 通过加强XIAP的活性降低恢复正常来治疗IBD。与鼠和 人类结肠类器官，我们将测试这样的想法，即在携带IBD相关的细胞中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患者中XIAP活性降低的原因。因此，在本发明中， 提高XIAP活性的策略可能具有广泛的影响，超出了XIAP突变所涉及的病例 在IBD。利用一种互补的方法，我们将使用专有的 一组我们已经鉴定的小分子“ARTS-拮抗剂”和“XIAP-激动剂”。我们力求提供 我们的“ARTS-拮抗剂”和“XIAP-激动剂”将能够使XIAP恢复正常， 在IBD相关XIAP突变的细胞中发挥作用，作为IBD的新治疗策略。我们还将测试 这些小分子在IBD动物模型中的作用。我们有两个具体的目标：（1）确定艺术的作用 在IBD中调节XIAP诱导的细胞凋亡和炎症，和（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 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 尚未对剥削进行调查。我们的长期目标是临床开发化合物， 逆转肠上皮细胞的损伤，促进粘膜愈合， IBD的治疗

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.