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:
- 金额:$ 22.55万
- 依托单位:
- 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:
- 关键词:ART proteinAffectAgonistAllelesAnimal ModelAnti-Tumor Necrosis Factor TherapyApoptosisBackBindingCaspase InhibitorCell DeathCell Death InductionCell LineCellsCessation of lifeCharacteristicsChronicChronic DiseaseCicatrixClinicalColonCrohn&aposs diseaseCytoprotectionDNA DamageDataDiseaseDisease modelDown-RegulationEpigenetic ProcessEpithelial CellsExhibitsFoodFoundationsGastrointestinal tract structureGenesGeneticGoalsHematopoietic SystemHost DefenseHumanImpairmentIncidenceInduction of ApoptosisInflammasomeInflammationInflammatoryInflammatory Bowel DiseasesInjuryInterleukinsIntestinal CancerIntestinal DiseasesIntestinesKnockout MiceLeadMethylationMolecularMucous MembraneMusMutationNatural regenerationOrganOrganoidsOutputPatientsPhenotypePhysiologicalPrevalencePreventionProteinsRNA SplicingRelapseResistanceRiskRoleStressSystemTNF geneTP53 geneTestingTherapeuticTranscriptional ActivationTumor Suppressor ProteinsUbiquitinUlcerative ColitisUp-RegulationVariantWorkantagonistclinical developmentcommensal microbescytokinegastrointestinal systemgut inflammationhealinghigh throughput screeninginnate immune pathwaysintestinal epitheliummicrobiotamouse modelmulticatalytic endopeptidase complexmutantnovelnovel strategiespreventpro-apoptotic proteinpromoterprotein expressionprotein functionreduce symptomsresponsesmall moleculesymptom treatmenttherapeutic targettreatment strategytumorubiquitin-protein ligasex-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
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 XIAP 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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Julie Magarian Blander其他文献
Julie Magarian Blander的其他文献
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