Mitigation of GI-ARS by Lactobacillus species
乳酸菌物种缓解 GI-ARS
基本信息
- 批准号:10570082
- 负责人:
- 金额:$ 48.78万
- 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:2022-12-22 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAnimal ModelAnti-Bacterial AgentsBacteriaBiologicalBiologyCaco-2 CellsCancer PatientCellsColonCyclic AMP-Dependent Protein KinasesCytoskeletonDataDietDoseDown-RegulationEffectivenessEndotoxemiaEpidermal Growth Factor ReceptorEpitheliumExhibitsExposure toFDA approvedFiltrationFunctional disorderGoalsHistone DeacetylaseHistone DeacetylationHourHumanIntestinal MucosaIntestinesIonizing radiationKnockout MiceLactic acidLactobacillusLactobacillus caseiLactobacillus plantarumMAPK8 geneMediatingMolecularMorbidity - disease rateMouse StrainsMucous MembraneMusNuclear AccidentsOral AdministrationOrganoidsOutcome StudyPaneth CellsPathogenesisPeptidesPlayPredispositionProbioticsProtein Kinase CProteinsQualifyingRadiationRadiation AccidentsRadiation EnteritisRadiation InjuriesRadiation ToxicityRadiation exposureResearchRoleSRC geneSurvival RateTestingTherapeuticTight JunctionsTimeTyrosine Phosphorylationalpha-Defensinsanimal ruleattenuationcancer radiation therapydysbiosisgastrointestinalgastrointestinal epitheliumgut dysbiosisgut microbiomegut microbiotainsect defensin Aintestinal barrierintestinal epitheliumirradiationknockout genemedical countermeasuremicrobiomemicrobiome alterationmicrobiome analysismicrobiotamonolayermortalitymouse modelnovelprobiotic therapyradiation mitigationradiation responsereceptors for activated C kinasesystemic inflammatory response
项目摘要
Public radiation exposure due to large-scale radiation incidents is a rising global concern. Gastrointestinal
Acute Radiation Syndrome (GI-ARS) is associated with high morbidity and mortality. However, FDA-
approved therapeutics for GI-ARS are unavailable. Therefore, outlining the mechanisms of radiation injury to
develop targeted medical countermeasures (MCMs) is a high priority. The gut microbiome is highly
susceptible to ionizing radiation, and an altered microbiome is a major contributing factor in the pathogenesis
of GI-ARS. The gap in this field is that the precise mechanisms by which radiation causes dysbiosis of gut
microbiota and its impact on radiation injury are poorly defined. The long-term goal of our research is to
identify the radiation-sensitive microbiota in the gut and develop gut microbiome-targeted MCMs to mitigate
radiation injury. Our preliminary studies have identified that: 1) Lactobacillus casei and plantarum mitigate
radiation-induced epithelial tight junction (TJ) disruption and barrier dysfunction by distinct cellular
mechanisms. 2) Depletion of Paneth cell α-defensins plays a pivotal role in the mechanism of radiation-
induced microbiota dysbiosis. 3) When administered in diet 24 hours after irradiation, L. casei and L. plantarum
mitigate radiation-induced α-defensin depletion, microbiota dysbiosis, gut barrier dysfunction, endotoxemia,
and systemic inflammation. These findings form the scientific premise and support the central hypothesis that
“L. casei and L. plantarum synergistically mitigate GI-ARS by reversing dysbiosis of gut microbiota and
epithelial barrier dysfunction, leading to attenuation of endotoxemia and systemic inflammation.” We
will test this hypothesis by determining that 1) L. plantarum mitigates radiation-induced epithelial TJ disruption
by EGFR-mediated inhibition of c-Jun N-terminal kinase-2 (JNK2)/c-Src/protein tyrosine phosphorylation, 2) L.
casei mitigates radiation-induced remodeling of the actin cytoskeleton and mucosal barrier dysfunction in the
intestinal epithelium by a PKC-dependent mechanism, 3) L. casei and L. plantarum synergistically mitigate
radiation-induced intestinal barrier dysfunction, 4) Radiation downregulates intestinal Paneth cell α-defensins
by HDAC3-mediated histone deacetylation, 5) HDAC3 and α-defensin downregulation play crucial roles in
radiation-induced dysbiosis of gut microbiota, 6) L. casei and L. plantarum, and their 3KDF fractions mitigate
radiation-induced HDAC3 expression, α-defensin depletion, and gut microbiota dysbiosis, 7) Identifying the
lowest effective doses of L. casei, L. plantarum, and 3KDF fractions for mitigating GI-ARS, 8) Determining the
ideal time window for the effectiveness of L. casei, L. plantarum, and 3KDF fractions, and 9) Determining the
most effective doses of L. casei and L. plantarum, and the ideal time window for increasing the survival rate
after lethal dose irradiation. Completing this project will establish a significant causative relation of intestinal
Lactobacillus depletion with radiation injury. Furthermore, these studies will validate Lactobacillus-based
probiotic therapy as a novel microbiome-targeted MCM for GI-ARS under the Animal-Rule guidance.
大规模辐射事件导致的公共辐射暴露是全球日益关注的问题。
然而,急性放射综合症(GI-ARS)与高发病率和死亡率相关。
目前还没有批准的 GI-ARS 治疗方法,因此,概述放射损伤的机制。
制定有针对性的医疗对策 (MCM) 是当务之急 肠道微生物组是高度优先事项。
易受电离辐射影响,微生物组的改变是发病机制的一个主要影响因素
该领域的空白在于辐射导致肠道菌群失调的精确机制。
微生物群及其对辐射损伤的影响尚不清楚。我们研究的长期目标是。
识别肠道中对辐射敏感的微生物群并开发针对肠道微生物群的 MCM 以缓解
我们的初步研究表明:1) 干酪乳杆菌和植物乳杆菌可减轻辐射损伤。
辐射诱导的上皮紧密连接(TJ)破坏和不同细胞的屏障功能障碍
2) 潘氏细胞α-防御素的消耗在辐射机制中起着关键作用。
3) 照射后 24 小时在饮食中施用时,干酪乳杆菌和植物乳杆菌。
辐射引起的α-防御素耗竭、微生物群失调、肠道屏障功能障碍、内毒素血症、
这些发现构成了科学前提并支持以下中心假设:
“干酪乳杆菌和植物乳杆菌通过逆转肠道菌群失调来协同减轻 GI-ARS
上皮功能障碍屏障,导致内毒素血症和全身炎症减轻。”
将通过确定 1) L. plantarum 减轻辐射诱导的上皮 TJ 破坏来检验这一假设
通过 EGFR 介导的 c-Jun N 末端激酶 2 (JNK2)/c-Src/蛋白酪氨酸磷酸化抑制,2) L.
干酪减轻放射诱导的肌动蛋白细胞骨架重塑和粘膜屏障功能障碍
通过 PKC 依赖性机制,3)协同减轻干酪乳杆菌和植物乳杆菌对肠上皮的影响
辐射引起的肠道屏障功能障碍,4)辐射下调肠潘氏细胞α-防御素
通过 HDAC3 介导的组蛋白脱乙酰化,5) HDAC3 和 α-防御素下调在
辐射引起的肠道微生物群失调,6) 干酪乳杆菌和植物乳杆菌及其 3KDF 分数得到缓解
辐射诱导的 HDAC3 表达、α-防御素耗竭和肠道微生物群失调,7) 识别
用于减轻 GI-ARS 的干酪乳杆菌、植物乳杆菌和 3KDF 组分的最低有效剂量,8) 确定
干酪乳杆菌、植物乳杆菌和 3KDF 组分有效性的理想时间窗口,以及 9) 确定
干酪乳杆菌和植物乳杆菌的最有效剂量,以及提高存活率的理想时间窗
完成致死剂量照射后,将建立肠道的显着因果关系。
此外,这些研究将验证基于乳酸菌的放射损伤。
益生菌疗法作为动物规则指导下针对 GI-ARS 的新型微生物组靶向 MCM。
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:
$ 48.78万 - 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:
$ 48.78万 - 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:
$ 48.78万 - 项目类别:
Intestinal Mucosal Protection by Epidermal Growth Factor
表皮生长因子对肠粘膜的保护
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8994319 - 财政年份:2015
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HYPOGLYCEMIA AND HYPERGLYCEMIA IN DEVELOPING BRAIN
大脑发育中的低血糖和高血糖
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8362842 - 财政年份:2011
- 资助金额:
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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
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$ 48.78万 - 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:
$ 48.78万 - 项目类别:
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