Mechanisms of Intestinal Integrity in Sepsis and Shock
Mechanisms of Intestinal Integrity in Sepsis and Shock
批准号:
10382790
负责人:
Craig M Coopersmith
金额:
$2.06万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2005
资助国家:
美国
项目状态:
已结题
起止时间:
2005-09-06 至 2023-08-31
关键词:
Adaptive Immune SystemAnimalsAntibiotic TherapyApoptosisBacteremiaBacteriaBiological AssayCause of DeathCellsChargeChronicCritical IllnessDangerousnessDataDiseaseDistantElementsEnterobacteriaceaeEnvironmentEpithelialEpithelial CellsEscherichia coliEvolutionFundingGeneticGoalsImmune responseImmune systemIntestinal permeabilityIntestinesLightMediatingMemoryMotorMovementMultiple Organ FailureMusMutationPathway interactionsPatientsPermeabilityPlayPneumoniaProcessProductionProliferatingProteinsPseudomonasPublic HealthRoleSepsisShockSupportive careTherapeuticTight JunctionsUnited StatesVillusbasececal ligation puncturecostgastrointestinal epitheliumimprovedinsightintestinal epitheliumjunctional adhesion moleculemicrobiomemicrobiome alterationmigrationmortalityprevent
中文摘要
脓毒症是美国重症患者死亡的主要原因,死亡人数在23万至25万之间
英文摘要
Sepsis is the leading cause of death among critically ill patients in the United States with between 230,000 and
370,000 people dying from the disease annually. Outside of antibiotics, treatment for sepsis is non-specific,
and there are no approved therapeutics available once antibiotics and supportive therapy fail. The gut has long
been characterized as the motor of multiple organ dysfunction syndrome. We have spent the three previous
cycles of funding examining mechanisms of gut integrity (first apoptosis then proliferation, migration and
permeability) in sepsis. This renewal is a logical next step in the evolution of how we view the gut in sepsis. We
propose to assay the intestinal epithelium, immune system and microbiome, both in isolation and also in the
context of how alterations in one compartment impact the others since we hypothesize this strategy will yield
insights that can only be obtained using this more comprehensive approach. The first goal of the proposal is to
understand mechanisms through which the immune system and microbiome alter survival in mice lacking the
tight junction-associated protein junctional adhesion molecule-A (JAM-A), which have alterations in
permeability, bacteremia and survival following sepsis. This will be done using a combination of mice with
whole body and intestine-specific deletion of JAM-A as well as mice with controlled alterations in the
endogenous bacteria. Further, intestinal permeability is controlled by two tight junction-dependent pathways
and a tight junction-independent pathway. Each allows different size molecules to exit the gut lumen into the
extraluminal environment. By genetically altering each of these pathways of permeability (the leak, pore and
unrestricted pathways respectively), studies will determine the functional significance of each together and in
isolation in sepsis. Finally, migration is slowed along the intestine during sepsis, with cells residing nearly twice
as long during sepsis as under basal conditions, mediated, at least in part, by apoptosis and proliferation.
Mechanisms of slowed migration will be determined including the impact of altering permeability and the
microbiome. Since the gut plays a major role in both initiating and propagating critical illness, understanding
mechanisms through which gut integrity is dysregulated in sepsis has significant public health implications in a
disease that is common, very costly, and highly lethal.
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DOI:
10.4049/jimmunol.1003391
发表时间:
2011-08-15
期刊:
Journal of immunology (Baltimore, Md. : 1950)
影响因子:
--
作者:
[Fox AC, Breed ER, Liang Z, Clark AT, Zee-Cheng BR, Chang KC, Dominguez JA, Jung E, Dunne WM, Burd EM, Farris AB, Linehan DC, Coopersmith CM]
通讯作者:
Coopersmith CM
DOI:
10.4049/jimmunol.1500218
发表时间:
2016-02-01
期刊:
Journal of immunology (Baltimore, Md. : 1950)
影响因子:
--
作者:
[Liu D, Burd EM, Coopersmith CM, Ford ML]
通讯作者:
Ford ML
The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia.
内源性细菌会改变肠道上的肠道凋亡,并在铜绿假单胞菌肺炎降低死亡率。
DOI:
10.1097/shk.0b013e31826e47e8
发表时间:
2012-11
期刊:
Shock (Augusta, Ga.)
影响因子:
--
作者:
[Fox AC, McConnell KW, Yoseph BP, Breed E, Liang Z, Clark AT, O'Donnell D, Zee-Cheng B, Jung E, Dominguez JA, Dunne WM, Burd EM, Coopersmith CM]
通讯作者:
Coopersmith CM
Comparison of time series clustering methods for identifying novel subphenotypes of patients with infection.
用于识别感染患者新亚表型的时间序列聚类方法的比较。
DOI:
10.1093/jamia/ocad063
发表时间:
2023
期刊:
Journal of the American Medical Informatics Association : JAMIA
影响因子:
--
作者:
[Bhavani,SivasubramaniumV, Xiong,Li, Pius,Abish, Semler,Matthew, Qian,EdwardT, Verhoef,PhilipA, Robichaux,Chad, Coopersmith,CraigM, Churpek,MatthewM]
通讯作者:
Churpek,MatthewM
DOI:
10.1097/shk.0000000000001163
发表时间:
2019-04
期刊:
Shock (Augusta, Ga.)
影响因子:
--
作者:
[Klingensmith NJ, Fay KT, Lyons JD, Chen CW, Otani S, Liang Z, Chihade DB, Burd EM, Ford ML, Coopersmith CM]
通讯作者:
Coopersmith CM
共 53 条
The Gut as a Target to Improve Outcomes in Sepsis
-
批准号:10552403
-
项目类别:
-
资助金额:$53.21万
-
财政年份:2023
-
负责人:Craig M Coopersmith
-
依托单位:
The Gut as a Target to Improve Outcomes in Sepsis
-
批准号:10797448
-
项目类别:
-
资助金额:$3.06万
-
财政年份:2023
-
负责人:Craig M Coopersmith
-
依托单位:
Targeting 2B4 Coinhibitory Signals During Sepsis-Induced Immune Dysregulation
-
批准号:8818803
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2015
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:10560545
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:9036407
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:8662516
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:10356019
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:10091965
-
项目类别:
-
资助金额:$35.1万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis
-
批准号:9260005
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2014
-
负责人:Craig M Coopersmith
-
依托单位:
The impact of cancer on the pathophysiology of sepsis
-
批准号:8822311
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2013
-
负责人:Craig M Coopersmith
-
依托单位:
The Impact of Cancer on the Pathophysiology of Sepsis
-
批准号:10189636
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2013
-
负责人:Craig M Coopersmith
-
依托单位:
The impact of cancer on the pathophysiology of sepsis
-
批准号:8667486
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2013
-
负责人:Craig M Coopersmith
-
依托单位:
The impact of cancer on the pathophysiology of sepsis
-
批准号:8425493
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2013
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:10090230
-
项目类别:
-
资助金额:$33.49万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:8291230
-
项目类别:
-
资助金额:$27.47万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:10441132
-
项目类别:
-
资助金额:$34.63万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:8501572
-
项目类别:
-
资助金额:$27.29万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:8017965
-
项目类别:
-
资助金额:$12.87万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:9291474
-
项目类别:
-
资助金额:$29.81万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
Critical Care Training Program
-
批准号:8690611
-
项目类别:
-
资助金额:$28.22万
-
财政年份:2011
-
负责人:Craig M Coopersmith
-
依托单位:
海外基金