Radiation-Induced Paneth Cell Dysfunction
辐射引起的潘氏细胞功能障碍
基本信息
- 批准号:10474225
- 负责人:
- 金额:$ 49.16万
- 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:2022-08-18 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Anti-Bacterial AgentsAttenuatedBacteriaBiologyBone MarrowCell physiologyClinicalColitisDataDefensinsDietDoseDown-RegulationEffectivenessEndotoxemiaEnterobacteriaceaeEpithelialEpithelial CellsExposure toFDA approvedFibroblastsFunctional disorderGoalsGrowthHomeostasisHumanImmuneImmune System DiseasesImpairmentInflammatory ResponseIntestinal MucosaIntestinesIonizing radiationKnockout MiceMediatingMessenger RNAMolecularMorbidity - disease rateMucosal Immune SystemMucosal ImmunityMucositisMucous MembraneMusNatural ImmunityOutcome StudyPaneth CellsPathogenesisPathway interactionsPeptidesProductionProtein IsoformsRNARadiationRadiation AccidentsRadiation Dose UnitRadiation InjuriesRadiation ToxicityRadiation exposureResearchRodentRoleSalmonella typhimuriumSmall IntestinesSupplementationSurvival RateT cell factor 4TestingTherapeuticTimeWNT Signaling Pathwayantimicrobial peptidebasecryptdindysbiosisfecal transplantationgastrointestinalgastrointestinal epitheliumgut dysbiosisgut microbiotainsect defensin Aintestinal cryptintestinal epitheliumirradiationmedical countermeasuremetatranscriptomemicrobiotamortalitymouse modelmultiorgan injurynovelpathobiontpathogenradiation effectresponsesubcutaneoussystemic inflammatory responsetranscription factor
项目摘要
Public exposure to radiation due to large-scale radiation incidents is a rising global concern. Acute
radiation syndrome (ARS) is associated with high morbidity and mortality, but no FDA-approved
therapeutics for gastrointestinal (GI) ARS. Therefore, delineating the mechanisms underlying radiation
injury to develop targeted medical countermeasures (MCM) is a high priority. The GI mucosal immune
system is susceptible to ionizing radiation, and dysfunctional mucosal immunity is a major contributing
factor in the pathogenesis of ARS. The gap in this field is that the precise mechanisms by which radiation
impairs the mucosal immune system and immune dysfunction-mediated dysbiosis of gut microbiota and
multi-organ injury (MOI) are poorly defined. The long-term goal of our research is to identify the radiation-
sensitive immune-specific pathways and test and develop novel immune dysfunction-targeted MCM for
radiation exposure. Endotoxemia and systemic inflammation are common conditions associated with
morbidity and mortality in ARS. Clinical and experimental evidence indicates that intestinal dysbiosis
(depleted beneficial species, increased pathobionts, and decreased diversity) is a prerequisite for
developing endotoxemia, systemic inflammation, and MOI. a-Defensins are antibacterial peptides secreted
from Paneth cells, the highly specialized intestinal epithelial cells, to maintain microbiota homeostasis.
Human Paneth cells produce two a-defensins - defensin 5 (HD5) and 6 (HD6). Our preliminary data show
that ionizing radiation in mouse intestine 1) depletes Paneth cell a-defensins, 2) reduces mucosal Tcf4
mRNA, 3) alters microbiota composition, 4) disrupts epithelial barrier, and 5) consequent mucosal
inflammatory response, endotoxemia, and systemic inflammation. Importantly, HD5 administered in the
diet at 24 h post-irradiation mitigates altered gut microbiota, gut barrier dysfunction, and endotoxemia.
These findings form the scientific premise (FIG 1) and support the central hypothesis that “HD5 mitigates
GI-ARS by reversing dysbiosis of gut microbiota and epithelial barrier dysfunction, leading to mitigation of
endotoxemia and systemic inflammation.” We will test this hypothesis by determining that 1) Ionizing
radiation downregulates Wnt signaling in intestinal Paneth cells, 2) TCF4 down-regulation mediates
radiation-induced a-defensin depletion and consequent dysbiosis, 3) a-Defensin supplementation reverses
radiation-induced dysbiosis of gut microbiota, 4) Radiation-induced dysbiosis drives gut barrier dysfunction,
endotoxemia, and systemic inflammation, 5) the lowest and most effective dose of HD5 in mitigating GI-
ARS, 6) the ideal time window for post-exposure (+24-96 h) effectiveness of HD5 to reverse GI-ARS, and
7) the HD5 treatment paradigm to increase the survival rates from lethal dose radiation.
.
由于大规模辐射事件造成的公众辐射暴露是一个日益引起全球关注的问题。急性
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)
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RADHAKRISHNA RAO其他文献
RADHAKRISHNA RAO的其他文献
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{{ truncateString('RADHAKRISHNA RAO', 18)}}的其他基金
Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage.
定义肠道钙通道在酒精性肝损伤中的作用。
- 批准号:
10390126 - 财政年份:2022
- 资助金额:
$ 49.16万 - 项目类别:
Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage.
定义肠道钙通道在酒精性肝损伤中的作用。
- 批准号:
10590757 - 财政年份:2022
- 资助金额:
$ 49.16万 - 项目类别:
Mitigation of GI-ARS by Lactobacillus species
乳酸菌物种缓解 GI-ARS
- 批准号:
10570082 - 财政年份:2022
- 资助金额:
$ 49.16万 - 项目类别:
Impact of Stress on Alcohol-Associated Gut Injury and Systemic Response
压力对酒精相关肠道损伤和全身反应的影响
- 批准号:
10485363 - 财政年份:2016
- 资助金额:
$ 49.16万 - 项目类别:
Intestinal Mucosal Protection by Epidermal Growth Factor
表皮生长因子对肠粘膜的保护
- 批准号:
8994319 - 财政年份:2015
- 资助金额:
$ 49.16万 - 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
- 批准号:
8362842 - 财政年份:2011
- 资助金额:
$ 49.16万 - 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
- 批准号:
8170447 - 财政年份:2010
- 资助金额:
$ 49.16万 - 项目类别:
HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
- 批准号:
7954982 - 财政年份:2009
- 资助金额:
$ 49.16万 - 项目类别:
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