Gene Regulatory Mechanisms Controlling Tissue Maturation and Polyploidization
Gene Regulatory Mechanisms Controlling Tissue Maturation and Polyploidization
批准号:
10396445
负责人:
Auinash Kalsotra
金额:
$18.78万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-04-22 至 2024-03-31
关键词:
AdultAffectAlternative SplicingAnimalsAutomobile DrivingBiochemistryBirthBuffersCell CycleCell NucleusCellsChromosomesCodeCommunitiesCompetenceCytokinesisDNA DamageDNA Sequence AlterationDevelopmentDiploidyEpithelialEventExhibitsExonsFailureFrequenciesFutureGene DosageGene ExpressionGenesGeneticGenetic TranscriptionGenomeGenomic approachGoalsHepaticHepatocarcinogenesisHepatocyteHumanInjuryKnockout MiceLinkLiverMammalsMetabolicMitosisMolecularMusMutationNatureNutritionalOrganOutcomeOutputOxidative StressPatternPhysiologicalPlantsPloidiesPolyploid CellsPolyploidyPrimary carcinoma of the liver cellsProductionPropertyProteinsProteomeRNA SplicingRNA-Binding ProteinsRegulator GenesResearchResolutionResourcesRodentRoleSpliced GenesTestingTimeTissuesTranscriptTumor Suppressor ProteinsVariantXenobioticscell typeexperimental studygenetic approachgenetic regulatory proteingenome-wideinsightliver developmentloss of functionmRNA Precursormouse modelnext generation sequencingpostnatalpostnatal periodprogramstranscriptometumorigenesis
中文摘要
I.摘要
多倍体是一种细胞携带两套以上染色体的状态,在自然界中经常观察到,
然而,控制倍性的遗传机制及其功能意义仍然是个谜。肝脏,在
特别是在出生后发育期获得高百分比的多倍体肝细胞;
肝多倍体化的频率和程度在损伤、DNA损伤和
氧化应激,但在肝细胞癌中降低。最近的证据表明,
通过减缓肝细胞的增殖能力和维持肝细胞的增殖能力,
肿瘤抑制剂的储存库。然而,对控制这些疾病的分子事件的了解很少。
出生后肝脏多倍化启动/促进或染色体倍性差异如何影响
肝细胞的转录和转录后活性。我们以前已经证明,
RNA结合蛋白ESRP 2是一个关键的发育调控因子,它激活一个成人剪接,
程序,以促进终末分化,功能能力和肝细胞的成熟。的目标
该建议的目的是(i)确定ESRP 2及其剪接的生理必要性/充分性-
调节网络在驱动肝细胞多倍体,和(ii)定义定量和定性的影响,
倍性对肝细胞转录输出的影响。Aim 1将使用ESRP 2功能获得和丧失小鼠模型,
确定通过ESRP 2激活的RNA剪接的程序性变化是否对
肝细胞的多倍化。在目标2中,我们将从二倍体和
多倍体小鼠肝细胞,以研究倍性如何影响稳态水平和替代
在全基因组范围内的肝转录本的剪接模式。拟议的目标将研究新的基因
控制多倍化的调节机制,同时发现以前未被认识到的
选择性剪接和细胞多倍性。
英文摘要
I. ABSTRACT
Polyploidy—a state in which cells carry more than two sets of chromosomes—is frequently observed in nature,
yet, the genetic mechanisms controlling ploidy and its functional significance remain enigmatic. The liver, in
particular, gains a high percentage of polyploid hepatocytes during postnatal period of development; and the
frequency and extent of hepatic polyploidization are further increased following injury, DNA damage, and
oxidative stress, but are decreased in hepatocellular carcinoma. Recent evidence suggests that polyploidy
safeguards the liver from tumorigenesis by slowing the proliferative capacity of hepatocytes and maintaining a
reservoir of tumor suppressors. However, there is minimal understanding of the molecular events that govern
the postnatal initiation/promotion of hepatic polyploidization or how differences in chromosomal ploidy affect
the transcriptional and posttranscriptional activities of hepatocytes. We have previously demonstrated that the
RNA binding protein ESRP2 is a key developmentally regulated factor, which activates an adult splicing
program to facilitate terminal differentiation, functional competence, and maturation of hepatocytes. The goals
of this proposal are to (i) determine the physiological necessity/sufficiency of ESRP2 and its splicing-
regulatory-network in driving hepatocyte polyploidy, and (ii) define the quantitative and qualitative impact of
ploidy on hepatocyte transcriptional output. Aim 1 will use ESRP2 gain-and loss-of-function mouse models to
determine if programmed changes in RNA splicing through ESRP2 activation are crucial for the
polyploidization of hepatocytes. In Aim 2, we will generate high-resolution transcriptomes from diploid and
polyploid murine hepatocytes to investigate how ploidy influences the steady-state levels and alternative
splicing patterns of hepatic transcripts at a genome-wide scale. The proposed aims will examine new gene
regulatory mechanism(s) controlling polyploidization while uncovering previously unrecognized links between
alternative splicing and cellular polyploidy.
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会议论文
Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development
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批准号:8859710
-
项目类别:
-
资助金额:$38.68万
-
财政年份:2015
-
负责人:Auinash Kalsotra
-
依托单位:
Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development
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批准号:10418690
-
项目类别:
-
资助金额:$38.56万
-
财政年份:2015
-
负责人:Auinash Kalsotra
-
依托单位:
Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development
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批准号:9233192
-
项目类别:
-
资助金额:$38.76万
-
财政年份:2015
-
负责人:Auinash Kalsotra
-
依托单位:
Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development
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批准号:10221031
-
项目类别:
-
资助金额:$38.56万
-
财政年份:2015
-
负责人:Auinash Kalsotra
-
依托单位:
Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development
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批准号:10642893
-
项目类别:
-
资助金额:$38.56万
-
财政年份:2015
-
负责人:Auinash Kalsotra
-
依托单位:
海外基金