Small molecule inhibitor of CD40 signaling for the control of inflammatory bowel disease
用于控制炎症性肠病的 CD40 信号小分子抑制剂
基本信息
- 批准号:10673011
- 负责人:
- 金额:$ 35.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAffinityAnimal ModelAnti-CD40AntibodiesBindingBiological AssayBlocking AntibodiesBlood PlateletsCell Adhesion MoleculesCellsClinical TrialsColitisCollaborationsDendritic CellsDiseaseDockingDoseEndothelial CellsEndotheliumEpithelial CellsGastrointestinal tract structureGeneticHistopathologyHumanIleitisImmune responseImpairmentIn VitroInfectionInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseIntercellular adhesion molecule 1Intestinal DiseasesIntestinesKnowledgeLeadLeukocytesLuciferasesMAPK1 geneMAPK11 geneMAPK8 geneMacrophageMediatingMedicineMicrosomesModelingMonoclonal AntibodiesMusOX40Opportunistic InfectionsOralPathway interactionsPatientsPermeabilityPhosphorylationPredispositionPropertyRPS6KA5 geneReceptor SignalingReporterResistanceRiskSeriesSignal TransductionSolubilityStructure-Activity RelationshipSystemT-LymphocyteTNF receptor-associated factor 3TNFRSF1A geneTNFRSF5 geneTNFRSF8 geneTNFSF5 geneTRADD geneTRAF2 geneTestingTherapeuticThromboembolismThrombosisTransgenic MiceTreatment ProtocolsTumor Necrosis Factor ReceptorUp-RegulationWorkanalogchemokinecrosslinkcytokinedesigndextran sulfate sodium induced colitiseffective therapyexperiencegut inflammationhigh throughput screeningimprovedin vivoinhibitorlead optimizationlymphotoxin beta receptormonocytemouse modelmurine colitisneutrophilnovelnovel strategiesnovel therapeutic interventionopportunistic pathogenpreventprogramsrecruitresponseside effectsmall moleculesmall molecule inhibitortreatment response
项目摘要
PROJECT SUMMARY
Despite advances in the treatment of inflammatory bowel disease (IBD), many patients fail to respond to
therapy. Thus, there is a need to find new therapeutic approaches against IBD. The CD40-CD154 pathway is a
known target against IBD and other inflammatory disorders. Clinical trials indicated that CD40 blockade with
anti-CD154 antibodies reduced inflammation. However, the anti-CD154 antibodies caused thrombosis
(unrelated to inhibition of CD40). Moreover, other approaches to cause global inhibition of CD40 are predicted
to increase the risk of opportunistic infections. Identification of a strategy to inhibit CD40-induced inflammation
that does not induce thrombosis or opportunistic infections can be a major advance in the treatment of IBD.
We uncovered that blocking the interaction between CD40 and an intracellular adaptor protein inhibits pro-
inflammatory responses induced by CD40 while leaving protection against an opportunistic pathogen intact.
We identified a small molecule that binds the adaptor protein, blocks CD40 signaling, reduces pro-
inflammatory responses in vitro and diminishes intestinal inflammation in mouse models of IBD. The compound
did not impair resistance against an opportunistic pathogen.
The compound has suboptimal solubility and microsomal stability. While some analogs designed to date
showed some improvement in solubility or microsomal stability, further optimization is necessary. The objective
of this application is to develop an optimized inhibitor that will be tested in mouse and human IBD systems.
The central hypothesis is that a potent analog with improved solubility and microsomal stability will optimally
block CD40 signaling, and markedly suppress inflammation in mouse models of IBD as well as CD40-driven
inflammatory responses in intestinal cells from patients with IBD. To test this hypothesis, we will design and
generate analogs of the compound, test their properties, perform signaling studies in reporter cells and
intestinal cells and test the lead inhibitor in animal models of IBD. In the first specific aim we will use structure
activity relationships with the aid of a docking model to design and generate analogs of the compound in order
to improve solubility and microsomal stability. We will examine their ability to inhibit CD40 signaling and their
affinity for the adaptor protein. In the second aim, we will test the most potent analogs to determine if they
inhibit CD40 signaling in vivo. In the third aim, we will determine if the lead analog reduces intestinal
inflammation in mouse models of IBD and inhibits CD40-induced expression of inflammatory molecules in
intestinal cells from IBD patients. The proposed work may lead to a new strategy to treat IBD based on a novel
approach to inhibit CD40 signaling.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
CARLOS S SUBAUSTE其他文献
CARLOS S SUBAUSTE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('CARLOS S SUBAUSTE', 18)}}的其他基金
Small molecule inhibitor of CD40 signaling for the control of inflammatory bowel disease
用于控制炎症性肠病的 CD40 信号小分子抑制剂
- 批准号:
10521673 - 财政年份:2022
- 资助金额:
$ 35.42万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 35.42万 - 项目类别:
Continuing Grant