CEACAM1 Alternative Splicing in Liver Ischemia-Reperfusion Injury
CEACAM1 选择性剪接在肝脏缺血再灌注损伤中的作用
基本信息
- 批准号:10622462
- 负责人:
- 金额:$ 54.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcuteAddressAdvocateAlternative SplicingAnti-Inflammatory AgentsAutophagocytosisBiological MarkersBiometryBiopsyBrain DeathCardiac DeathCell Culture SystemCell DeathCellsClinicalComplementComplement component C1CryopreservationCytoplasmCytoprotectionDataExclusionExonsGenesHepaticHepatic TissueHepatocyteHumanImmuneImpairmentInfiltrationInflammationInjuryInterventionIschemiaLifeLiverLymphocyteMAP Kinase GeneMacrophageMediatingMessenger RNAMucosal ImmunityMusMyelogenousNatural ImmunityNatural regenerationOperative Surgical ProceduresOrganOrgan DonorOrgan PreservationOrgan TransplantationOutcomePathway interactionsPatientsPhasePhenotypeProtein IsoformsRNA SplicingRecoveryRegulationRejuvenationReperfusion InjuryReportingResistanceResolutionSentinelSignal TransductionSterilityStressTissuesTransgenic MiceTransplantationTransplantation SurgeryVariantWaiting ListsWarm Ischemiacarcinoembryonic antigen-related cell adhesion moleculesclinically relevantend stage liver diseaseexperimental studyfunctional improvementimmunoregulationimprovedinsightliver functionliver inflammationliver ischemialiver transplantationmortalitymouse modelneutrophilnovelnovel therapeuticsp38 Mitogen Activated Protein Kinasepreservationpreventprogramsregenerativerepairedscreeningstandard of caresuccesssynergismtransplant model
项目摘要
PROJECT 1 – SUMMARY/ABSTRACT
Project 1 competitive renewal addresses the unmet clinical and scientific needs to enhance donor liver supply
through organ “rejuvenation.” We reported that hepatic CEACAM1 (encoded by CC1 gene; CD66a) dictates
donor liver quality, and prevents early OLT injury in mice and humans. CC1 mRNA undergoes alternative splicing
(AS) to generate splice variants, characterized by the inclusion (CC1-L; long) or exclusion (CC1-S; short) of exon
7. Hypothesis: Hepatocyte CC1-S functions as a cytoprotective sentinel, while CC1-L in OLT-infiltrating recipient-
derived neutrophils, regulates liver IR-inflammation and fine-tunes its resolution.
Aim 1: Delineate mechanisms by which hepatic CC1-S isoform promotes cellular protection in IR-
stressed mouse OLT. Hypothesis: Antisense oligomer morpholinos (MOs)-enforced AS of hepatic CC1
generates CC1-S isoform in the donor mouse liver, which under the control of HIF-1α, stimulates cytoprotection
by blocking p-p38 (under cold IR-stress) while promoting GPX4 and targeting ferroptosis (under warm IR-stress).
Here, we will ascertain whether 1.1: CC1-AS accelerates otherwise impaired hepatic recovery in the acute and
the resolution phase of IR-inflammation. 1.2: CC1-S controls IRI-OLT by regulating hepatic cell death pathways.
1.3: CC1-S-mediated cytoprotection is controlled by HIF-1α signaling under warm vs. cold hepatic IR-stress.
Aim 2: Define mechanisms by which neutrophil CC1-L isoform exerts anti-inflammatory and
cytoprotective functions in IR-stressed mouse OLT. Hypothesis: Recipient CC1-L neutrophils counteract acute
IRI-OLT, and stimulate inflammation resolution by orchestrating N1/N2 polarization, with resultant liver
homeostatic/regenerative remodeling. We will study whether 2.1: Recipient CC1-L deficient immune cells
exacerbate hepatic IRI-OLT. 2.2: CC1-L polarizes N2 neutrophils to promote an anti-inflammatory phenotype/
improve OLT outcomes. 2.3: CC1-L proficient neutrophils polarize M2 macrophages/promote hepatic autophagy.
Aim 3: Elucidate mechanisms by which hepatic CC1-S isoform rejuvenates discarded human livers
subjected to normothermic machine preservation (NMP). Hypothesis: NMP, supplemented with HIF-1α – CC1-
S axis modifiers, improves the function of discarded human livers by mitigating ferroptosis while promoting
autophagy. We will incorporate the emerging NMP strategy with adjunctive CC1-intervention to assess whether
3.1: MOs-conditioned humanized CC1 transgenic mice (huCC1-Tg) mimic the effects of CC1-AS upon liver IR-
stress in normal mice but be translatable to the human liver. 3.2: CC1-S isoform synergizes with HIF-1α to
improve liver function. 3.3: CC1-S synergizes with HIF-1α to enhance cytoprotection in human livers.
Integration with PPG: Project 1 complements studies assessing homeostatic mechanisms in the
resolution of IRI-OLT in Project 2. Aim 1-2 in Project 1 will be validated by the screening of human OLT biopsies
to accelerate assessments of clinical innate immune phenotypes in Project 3. Project 1 is dependent on Core A
(Administrative), Core B (Mouse and Human OLT Surgery), and Core C (Computational and Biostatistics).
项目1 - 摘要/摘要
项目1竞争性更新解决了未满足的临床和科学需求,以增强供体肝脏供应
通过器官“复兴”。我们报道说肝癌CeCAM1(由CC1基因编码; CD66A)决定了
供体肝脏质量,并防止小鼠和人类的早期OLT损伤。 CC1 mRNA经历替代剪接
(AS)生成剪接变体,其特征是外显子的包含(CC1-L; Long)或排除(CC1-S; Short)
7。假设:肝细胞CC1-S充当细胞保护前哨,而CC1-L在OLT渗透受体中 -
衍生的中性粒细胞,调节肝脏IR炎症并微调其分辨率。
AIM 1:描述肝CC1-S同工型促进IR-的细胞保护的机制
压力小鼠OLT。假设:反义低聚物形态(MOS) - 肝CC1
在HIF-1α的控制下,在供体小鼠肝脏中生成CC1-S同工型,刺激细胞保护
通过阻止P-p38(在冷ir应力下),同时促进GPX4并靶向铁铁作用(在温暖的IR压力下)。
在这里,我们将确定1.1:cc1- as是否会加速急性中的肝恢复受损
IR炎症的分辨率阶段。 1.2:CC1-S通过控制肝细胞死亡途径来控制iri-olt。
1.3:CC1-S介导的细胞保护受到HIF-1α信号传导的控制,在温暖的肝脏IR应力下。
AIM 2:定义中性粒细胞CC1-L同工型施加抗炎和的机制
IR压力小鼠OLT中的细胞保护功能。假设:接受者CC1-L中性粒细胞抵消急性
iri-olt,并通过策划N1/N2极化来刺激注射分辨率,从而导致肝脏
稳态/再生重塑。我们将研究2.1:受体CC1-L缺乏免疫细胞
加剧肝iri-olt。 2.2:CC1-L对N2中性粒细胞两极化,以促进抗炎表型/
改善OLT结果。 2.3:CC1-L熟练的中性粒细胞极化M2巨噬细胞/促进肝自噬。
AIM 3:阐明肝CC1-S同工型恢复原状的机制
受到常规机器保存(NMP)的约束。假设:NMP,补充了HIF-1α - CC1-
S轴修饰符,通过减轻促进性铁的作用来改善被丢弃的人类生命的功能
自噬。我们将将新兴的NMP策略与辅助CC1干预结合在一起,以评估是否是否
3.1:MOS结构的人源化CC1转基因小鼠(HUCC1-TG)模仿CC1-AS对肝脏IR-的影响
正常小鼠的压力,但可以翻译成人肝。 3.2:CC1-S同工型与HIF-1α协同作用
3.3:CC1-S与HIF-1α协同作用,以增强人类生命中的细胞保护作用。
与PPG集成:项目1完成了评估稳态机制的研究
项目2中的iri-olt的决议。项目1中的目标1-2将通过筛选人类OLT活检来验证
在项目3中加速评估临床先天免疫表型。项目1取决于核心A
(行政),核心B(小鼠和人类OLT手术)和核心C(计算和生物统计学)。
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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Jerzy W Kupiec-Weglinski其他文献
Jerzy W Kupiec-Weglinski的其他文献
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{{ truncateString('Jerzy W Kupiec-Weglinski', 18)}}的其他基金
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
- 批准号:
10101174 - 财政年份:2020
- 资助金额:
$ 54.09万 - 项目类别:
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
- 批准号:
10685284 - 财政年份:2020
- 资助金额:
$ 54.09万 - 项目类别:
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
- 批准号:
10472636 - 财政年份:2020
- 资助金额:
$ 54.09万 - 项目类别:
THE RELAXIN RECEPTOR GR/RXFP1 SIGNALING IN LIVER TRANSPLANT ISCHEMIA-REPERFUSION INJURY AND THE INFLAMMATION RESOLUTION
松弛素受体 GR/RXFP1 信号在肝移植缺血再灌注损伤和炎症消退中的作用
- 批准号:
10268216 - 财政年份:2020
- 资助金额:
$ 54.09万 - 项目类别:
Innate-Adaptive Immune Interface in Liver Ischemia-Reperfusion Injury
肝脏缺血再灌注损伤中的先天适应性免疫界面
- 批准号:
9975698 - 财政年份:2017
- 资助金额:
$ 54.09万 - 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
- 批准号:
9359428 - 财政年份:2017
- 资助金额:
$ 54.09万 - 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
- 批准号:
9975685 - 财政年份:2017
- 资助金额:
$ 54.09万 - 项目类别:
Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury
肝移植缺血/再灌注损伤中的先天适应性免疫调节
- 批准号:
9750602 - 财政年份:2017
- 资助金额:
$ 54.09万 - 项目类别:
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