Microbiota metabolites SCFA promote intestinal epithelial repair and wound healing
微生物代谢物 SCFA 促进肠上皮修复和伤口愈合
基本信息
- 批准号:9760793
- 负责人:
- 金额:$ 3.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAcuteAddressAffectAnti-inflammatoryApoptosisApoptoticAttenuatedBiological AssayButyratesCRISPR/Cas technologyCell Differentiation processCell LineCellsClinicalClinical TrialsColectomyColitisColorectal CancerComplexConfocal MicroscopyDataDendritic CellsDevelopmentDietDietary FiberDiseaseDisease remissionEGF geneEpithelialEpithelial CellsExperimental ModelsFOXP3 geneFermentationFlow CytometryFutureGene ExpressionGenesGlycoproteinsGoalsHealthHistone Deacetylase InhibitorHomeostasisHumanImmunohistochemistryIn VitroIncidenceInflammationInflammatory Bowel DiseasesIntestinesKnockout MiceKnowledgeLeadLinkModelingMolecular Biology TechniquesMorbidity - disease rateMucous MembraneMusNatural regenerationNecrosisOperative Surgical ProceduresPathogenesisPathway interactionsPatientsPhagocytosisPhenotypePhosphotransferasesPlayProcessProductionPropionatesProteinsProto-Oncogene Proteins c-aktPublic HealthQuantitative Reverse Transcriptase PCRRecombinantsRegulationRegulatory T-LymphocyteResearch Project GrantsRiskRoleStem cellsT cell differentiationTherapeuticUp-RegulationVolatile Fatty AcidsWestern BlottingWound Healingcell motilitycell typecolorectal cancer riskconditioningcytokinegut microbiotaimmunoregulationin vitro Assayin vivointestinal homeostasismacrophagemicrobialmicrobiota metabolitesmigrationmilk expressionmilk fat globulemortalitynew therapeutic targetnovelnovel therapeuticspre-clinical researchpreventreceptorrepairedtargeted treatmenttherapeutic developmenttherapeutic target
项目摘要
ABSTRACT
Inflammatory bowel disease (IBD) is a sizable health challenge that has emerged in the 21st century, affecting
millions of people worldwide with incidence rates on the rise. Current therapies are insufficient to induce long-
term remission in many patients, leading to high rates of surgical intervention and increased risk of colorectal
cancer (CRC). Thus, new therapies are needed to decrease morbidity and mortality from IBD. Many patients
with IBD are deficient in the microbial metabolites of dietary fibers, short chain fatty acids (SCFAs), and thus
SCFAs represent a potential target for therapeutic development. SCFAs play complex roles in gut homeostasis
including epithelial turnover, proliferation, apoptosis, and immune regulation. SCFAs have a profound impact
on human health and disease, and a diet high in dietary fibers has been linked to decreased risk of CRC and
IBD. To date, the evidence for use of SCFAs as a treatment for IBD has been inconsistent. These
inconsistencies are most likely driven by SCFAs ability to regulate gene expression by inhibition of histone
deacetylases; however, which genes are differentially regulated is largely dependent on the type of SCFA, its
concentration relative to other SCFAs, and the cell type, all of which further complicate treatment. To date, the
identity of the specific genes that are differentially regulated by SCFAs to induce wound healing and modulate
inflammation are unknown. Recently, we identified a secreted glycoprotein, milk fat globule-EGF factor 8
(MFGE8), which is significantly upregulated by SCFAs. MFGE8 is deficient in IBD patients, and plays roles in
cellular migration and T cell differentiation. Thus, the long-term goal of this project is to understand the role of
SCFAs in the promotion of migration and suppression of inflammation, key processes in wound healing and
protection against colitis. Our hypothesis is that SCFAs differentially regulate intestinal epithelial cell
(IEC) expression of MFGE8 to induce wound healing and suppress inflammation in IBD. Using MFGE8
deficient cell lines and KO mice, we will employ several molecular biology techniques including wound healing
assays, immunohistochemistry, confocal microscopy, kinase assays, ex. vivo enteroid cultures, flow cytometry,
and acute and transfer models of experimental colitis to address our hypothesis through two specific aims: 1)
Define the role of MFGE8 in SCFA-induced wound healing; 2) Determine SCFA conditioning of IEC to
induce Treg development through induction of MFGE8. Elucidating the roles of MFGE8 in SCFA induction
of wound healing and suppression of inflammation in IBD will help deepen our understanding of the potential of
SCFAs as a therapeutic. This information will be utilized to inform future therapeutic development involving
SCFAs, and ultimately remove a critical barrier that is preventing long-term sustained remission in a large
percentage of IBD patients.
!
抽象的
炎症性肠病(IBD)是21世纪出现的重大健康挑战,影响
全世界有数百万的人,发病率上升。当前的疗法不足以诱导长期
许多患者的期限缓解,导致手术干预率很高,大肠风险增加
癌症(CRC)。因此,需要新的疗法来降低IBD的发病率和死亡率。许多患者
与IBD有关饮食纤维,短链脂肪酸(SCFA)的微生物代谢不足,因此
SCFA代表了治疗发展的潜在目标。 SCFA在肠内稳态中扮演复杂的角色
包括上皮周转,增殖,凋亡和免疫调节。 SCFA具有深远的影响
关于人类健康和疾病以及饮食纤维高的饮食与CRC的风险降低有关
IBD。迄今为止,使用SCFA作为IBD治疗的证据一直不一致。这些
不一致很可能是由于SCFA通过抑制组蛋白调节基因表达的能力而驱动的
脱乙酰基酶;但是,哪些基因受差异调节在很大程度上取决于SCFA的类型
相对于其他SCFA和细胞类型的浓度,所有这些都进一步使治疗复杂化。迄今为止,
由SCFA差异调节以诱导伤口愈合和调节的特定基因的身份
炎症是未知的。最近,我们确定了一种分泌的糖蛋白,牛奶脂肪球-EGF因子8
(MFGE8),它被SCFA显着上调。 MFGE8缺乏IBD患者,并且在
细胞迁移和T细胞分化。因此,该项目的长期目标是了解
SCFA在促进迁移和抑制炎症,伤口愈合中的关键过程和
保护结肠炎。我们的假设是SCFA差异调节肠上皮细胞
(IEC)MFGE8的表达以诱导伤口愈合并抑制IBD的炎症。使用MFGE8
缺乏细胞系和KO小鼠,我们将采用几种分子生物学技术,包括伤口愈合
测定,免疫组织化学,共聚焦显微镜,激酶测定,例如。体内肠培养基,流式细胞仪,
以及实验性结肠炎的急性和转移模型,通过两个特定目的解决我们的假设:1)
定义MFGE8在SCFA诱导的伤口愈合中的作用; 2)确定IEC的SCFA条件至
通过诱导MFGE8诱导Treg的发展。阐明MFGE8在SCFA诱导中的作用
IBD中伤口愈合和抑制炎症的抑制将有助于加深我们对
SCFA作为治疗性。这些信息将用于告知未来的治疗发展,涉及
SCFA,并最终消除了一个关键障碍,该障碍阻止了大型长期持续缓解
IBD患者的百分比。
呢
项目成果
期刊论文数量(0)
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Anthony J Bilotta其他文献
Anthony J Bilotta的其他文献
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{{ truncateString('Anthony J Bilotta', 18)}}的其他基金
Microbiota metabolites SCFA promote intestinal epithelial repair and wound healing
微生物代谢物 SCFA 促进肠上皮修复和伤口愈合
- 批准号:
9892872 - 财政年份:2019
- 资助金额:
$ 3.36万 - 项目类别:
Microbiota metabolites SCFA promote intestinal epithelial repair and wound healing
微生物代谢物 SCFA 促进肠上皮修复和伤口愈合
- 批准号:
10347334 - 财政年份:2019
- 资助金额:
$ 3.36万 - 项目类别:
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