Mechanisms of Polyploidy and Aneuploidy in the Liver
肝脏多倍体和非整倍体的机制
基本信息
- 批准号:8796891
- 负责人:
- 金额:$ 43.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-25 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAmericanAneuploid CellsAneuploidyBiologyCause of DeathCell divisionCell physiologyCellsChromosome SegregationChromosomesChronicDataDevelopmentDiploidyDiseaseDisease ResistanceGene ExpressionGenesGenomeGoalsHepaticHepatocyteHomeostasisHumanIndividualInjuryKnockout MiceLaboratoriesLifeLiverLiver DysfunctionLiver RegenerationLiver diseasesMammalsMeasuresMediatingMicroRNAsModelingMolecularMolecular ProfilingMusNatural regenerationNoduleOrganOrganismPhysiologicalPloidiesPolyploidyProcessResearchRoleSignal TransductionSteatohepatitisTestingTherapeuticTissue-Specific Gene ExpressionTyrosinemiasVariantViral hepatitisXenograft procedureYeastsbasebiological adaptation to stresscell typechronic liver diseaseimprovedinnovationinsightliver functionliver injuryliver repairmouse modelnovelpostnatalpublic health relevanceregenerativeresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Nearly 25 million Americans are affected by liver dysfunction, and liver diseases are the 10th leading cause of death in the US. There is a clear and urgent need for developing new alternatives to whole organ replacement. A better understanding of liver biology is required to improve existing approaches and to innovate therapies for the treatment of liver diseases, including viral hepatitis and steatohepatitis. Hepatocytes, the primary functional cell type in the liver, display a range of chromosomal diversity resulting from prevalent physiological polyploidy (>90% in mice and 50% in humans) and aneuploidy (60% in mice and 30-90% in humans). In eukaryotic organisms, cells usually contain a diploid genome comprised of pairs of homologous chromosomes. Polyploidy refers to gains in entire sets of chromosomes, and aneuploidy refers to gains and losses of individual chromosomes. The roles of hepatic polyploidy and aneuploidy represent a major gap in our current understanding of liver biology. We recently found that aneuploidy enhances the regenerative capacity of the mouse liver. In response to Tyrosinemia-induced injury, that is normally toxic to the liver, we identified a subset of aneuploid hepatocytes that was resistant to the disease. The data suggest that aneuploid hepatocytes are endowed with enhanced capacity for adaptation and regeneration. Our central hypothesis is that aneuploidy functions as an adaptive mechanism in response to hepatic injury. The goals of this application are to identify mechanisms regulating hepatic aneuploidy/polyploidy and to unravel how aneuploidy affects liver function. To investigate these questions, we propose in Specific Aim 1 to determine whether polyploid hepatocytes are necessary for development of aneuploid livers. Experiments will characterize hepatic cell divisions, karyotypes and stress response in E2f7/E2f8 knockout mice, which have normal liver function but are depleted of polyploid hepatocytes. In Specific Aim 2, we will dissect the role of a novel regulator of hepatic polyploidy, recently identified in ur laboratory, microRNA-122 (miR-122). Experiments will determine how miR-122 alters ploidy and aneuploidy throughout life. We will also identify cellular and molecular mechanisms by which miR-122 regulates hepatic ploidy. Finally, in Specific Aim 3, we will determine how random karyotypes (in aneuploid hepatocytes) affect function in the liver. We will utilize a novel xenotransplantation model to examine clonal nodules of regenerating human hepatocytes. Experiments will measure aneuploidy and determine gene expression profiles in these nodules. Together, these studies will define the extent to which aneuploidy affects liver repair/regeneration as well as the molecular mechanisms that control this process. Understanding how aneuploid hepatocytes arise and function will provide new and crucial insights into liver homeostasis, diseases and treatments.
描述(由申请人提供):近 2500 万美国人受到肝功能障碍的影响,肝病是美国第十大死因。显然迫切需要开发全器官替代的新替代方案。需要更好地了解肝脏生物学,以改进现有方法并创新治疗肝脏疾病(包括病毒性肝炎和脂肪性肝炎)的疗法。肝细胞是肝脏中的主要功能细胞类型,显示出一系列由普遍的生理多倍性(小鼠中 >90%,人类中 50%)和非整倍性(小鼠中 60%,人类 30-90%)引起的染色体多样性。在真核生物中,细胞通常含有由成对同源染色体组成的二倍体基因组。多倍体是指整组染色体的增加,非整倍体是指单个染色体的增加和损失。肝脏多倍体和非整倍体的作用代表了我们目前对肝脏生物学理解的一个主要差距。我们最近发现非整倍体增强了小鼠肝脏的再生能力。为了应对酪氨酸血症引起的损伤(通常对肝脏有毒),我们鉴定了一个对这种疾病具有抵抗力的非整倍体肝细胞子集。数据表明,非整倍体肝细胞具有增强的适应和再生能力。我们的中心假设是非整倍体作为响应肝损伤的适应性机制发挥作用。该应用的目标是确定调节肝脏非整倍体/多倍体的机制,并揭示非整倍体如何影响肝功能。为了研究这些问题,我们在具体目标 1 中建议确定多倍体肝细胞对于非整倍体肝脏的发育是否是必需的。实验将表征 E2f7/E2f8 敲除小鼠的肝细胞分裂、核型和应激反应,这些小鼠具有正常的肝功能,但缺乏多倍体肝细胞。在具体目标 2 中,我们将剖析我们实验室最近发现的一种新型肝多倍体调节因子 microRNA-122 (miR-122) 的作用。实验将确定 miR-122 如何在一生中改变倍性和非整倍性。我们还将确定 miR-122 调节肝倍性的细胞和分子机制。最后,在具体目标 3 中,我们将确定随机核型(在非整倍体肝细胞中)如何影响肝脏功能。我们将利用一种新型异种移植模型来检查再生人肝细胞的克隆结节。实验将测量非整倍性并确定这些结节中的基因表达谱。这些研究将共同确定非整倍性影响肝脏修复/再生的程度以及控制这一过程的分子机制。了解非整倍体肝细胞的产生和功能将为肝脏稳态、疾病和治疗提供新的、重要的见解。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ANDREW W DUNCAN其他文献
ANDREW W DUNCAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ANDREW W DUNCAN', 18)}}的其他基金
Mechanisms of Polyploidy and Aneuploidy in the Liver
肝脏多倍体和非整倍体的机制
- 批准号:
10548883 - 财政年份:2014
- 资助金额:
$ 43.53万 - 项目类别:
Mechanisms of Polyploidy and Aneuploidy in the Liver
肝脏多倍体和非整倍体的机制
- 批准号:
8931964 - 财政年份:2014
- 资助金额:
$ 43.53万 - 项目类别:
Mechanisms of Polyploidy and Aneuploidy in the Liver
肝脏多倍体和非整倍体的机制
- 批准号:
10339419 - 财政年份:2014
- 资助金额:
$ 43.53万 - 项目类别:
Cellular Approaches to Tissue Engineering and Regeneration
组织工程和再生的细胞方法
- 批准号:
10663265 - 财政年份:2003
- 资助金额:
$ 43.53万 - 项目类别:
相似国自然基金
HTRA1介导CTRP5调控脂代谢通路在年龄相关性黄斑变性中的致病机制研究
- 批准号:82301231
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
PLAAT3降低介导线粒体降解异常在年龄相关性白内障发病中的作用及机制
- 批准号:82301190
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
跨尺度年龄自适应儿童头部模型构建与弥漫性轴索损伤行为及表征研究
- 批准号:52375281
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
ALKBH5通过SHP-1调控视网膜色素上皮细胞铁死亡在年龄相关性黄斑变性中的作用机制研究
- 批准号:82301213
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
视网膜色素上皮细胞中NAD+水解酶SARM1调控自噬溶酶体途径参与年龄相关性黄斑变性的机制研究
- 批准号:82301214
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Executive functions in urban Hispanic/Latino youth: exposure to mixture of arsenic and pesticides during childhood
城市西班牙裔/拉丁裔青年的执行功能:童年时期接触砷和农药的混合物
- 批准号:
10751106 - 财政年份:2024
- 资助金额:
$ 43.53万 - 项目类别:
Fluency from Flesh to Filament: Collation, Representation, and Analysis of Multi-Scale Neuroimaging data to Characterize and Diagnose Alzheimer's Disease
从肉体到细丝的流畅性:多尺度神经影像数据的整理、表示和分析,以表征和诊断阿尔茨海默病
- 批准号:
10462257 - 财政年份:2023
- 资助金额:
$ 43.53万 - 项目类别:
Previvors Recharge: A Resilience Program for Cancer Previvors
癌症预防者恢复活力计划:癌症预防者恢复力计划
- 批准号:
10698965 - 财政年份:2023
- 资助金额:
$ 43.53万 - 项目类别:
Impact of Mitochondrial Lipidomic Dynamics and its Interaction with APOE Isoforms on Brain Aging and Alzheimers Disease
线粒体脂质组动力学及其与 APOE 亚型的相互作用对脑衰老和阿尔茨海默病的影响
- 批准号:
10645610 - 财政年份:2023
- 资助金额:
$ 43.53万 - 项目类别:
Role of YB1 in health disparities in triple negative breast cancer
YB1 在三阴性乳腺癌健康差异中的作用
- 批准号:
10655943 - 财政年份:2023
- 资助金额:
$ 43.53万 - 项目类别: