A new hypothesis: role of p53 inhibitory factors in cellular reprogramming
A new hypothesis: role of p53 inhibitory factors in cellular reprogramming
批准号:
8632184
负责人:
Kitai Kim
金额:
$46.5万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-09-30 至 2019-04-30
关键词:
ATM promoterAgeAgingApoptoticBindingCell LineCell physiologyCellsCentromereChromosomal InstabilityChronicDNA DamageDegenerative DisorderDevelopmentEctopic ExpressionEmbryoEpigenetic ProcessEthicsFibroblastsGenesGenome StabilityGenomic InstabilityGenomicsGoalsHumanImmune systemIn VitroIndividualLeadLegal patentMAPK9 geneMalignant NeoplasmsMolecular AbnormalityMutationOncogenicOocytesPLK1 genePathway interactionsPatientsPhenotypePhosphorylationPluripotent Stem CellsPopulationRegenerative MedicineReplacement TherapyReportingResearchResidual stateRoleSomatic CellSourceStem cellsSystems BiologyTestingTissue DonorsTissue TransplantationTissuesage effectage relatedagedcell typeclinical applicationcomparativeembryonic stem cellgenome-widehistone modificationimprovedin vivoinduced pluripotent stem cellinnovationinsightmouse modelnormal agingolder patientpluripotencypressurepublic health relevanceresponsetissue regenerationtool
中文摘要
项目概要/摘要
在各种多能干细胞中,诱导性多能干细胞(iPSC)-通过异位诱导产生。
四种胚胎重编程基因在体细胞中的表达-提供了患者特异性干细胞的来源
没有与胚胎干细胞(ESC)相关的伦理限制的细胞。然而,我们和其他人
报道iPSC是不完全重编程的,我们发现重编程的程度
随着供体组织的老化而减少。我们的总体研究目标是改善
iPSC以产生用于移植的高质量的患者特异性组织相容性组织。因为
老年患者更有可能从iPSC的临床应用中受益,因此,
全面评估来源于较老供体细胞的iPSC(A-iPSC),并鉴定额外的多能干细胞,
这些重编程因子可以逆转衰老对A-iPSC重编程的负面影响。多
有报道提出,p53是体细胞重编程的负调节因子,
p53增加iPSC重编程效率。然而,基础p53水平在ESC和iPSC中升高,
与体细胞相比,导致我们提出一个创新的假设-iPSC重编程是
由于p53抑制因子对升高的p53的抑制不足而不完全。我们进一步假设
A-iPSC可能无法激活这些假定的p53抑制因子来克服升高的p53
在iPSC重编程过程中结果,p53不能被完全抑制,并且残留的p53活性
刺激组成性DNA损伤反应,该反应模拟通常仅在响应于DNA损伤时发生的反应。
遗传毒性的侮辱慢性DNA损伤反应(通过p53依赖性和非依赖性途径)
在体细胞的正常老化过程中观察到,并可导致DNA损伤的完全丧失。
癌症发展过程中的反应。我们假设整个DNA损伤的表观遗传破坏
反应将改善A-iPSC重编程和质量。在初步研究中,我们检查了
两个假定的p53抑制因子,并使用这些因子来鉴定多能调节因子,
纠正衰老相关的表观遗传景观并提高A-iPSC的质量。在本提案中,我们将
通过进行全面的比较,检查这些多能调节因子的功能,
分析这些iPSC类型。在目标1中,我们将确定多能调节性细胞的机制。
这些因素逆转了异常DNA损伤反应和衰老对A-iPSC表型的负面影响。在
目的2,我们将确定多能调节因子的功能作用,通过比较,
在几个体外和体内测试中,每个细胞系的多能性和分化潜力。最终,我们
这些发现将为我们如何提高患者特异性干细胞的质量提供重要的见解。
用于组织再生和移植。
公共卫生相关性
使用个体专利衍生的iPSC的再生医学具有产生
组织相容性可移植组织;这种方法将特别有利于老年人,
可能患有退行性疾病最终,我们的发现和拟议的研究将提供关键的见解,
我们如何提高从老年患者中提取的患者特异性干细胞的质量,
再生和移植。
英文摘要
Project Summary/Abstract
Among the various pluripotent stem cells, induced pluripotent stem cells (iPSC)-generated by ectopic
expression of four embryonic reprogramming genes in somatic cells-provide a source of patient-specific stem
cells without the ethical limitations associated with embryonic stem cells (ESC). However, we and others have
reported that iPSC are incompletely reprogrammed, and we found that the degree of reprogramming
decreases with the age of the donor tissue. Our overall research goal is to improve the reprogramming of
iPSC in order to produce high-quality patient-specific histocompatible tissues for transplantation. Because
older patients are more likely to benefit from the clinical applications of iPSC, there is a significant need to
comprehensively evaluate iPSC derived from older donor cells (A-iPSC) and identify additional pluripotent
reprogramming factors that can reverse the negative impact of aging on A-iPSC reprogramming. Multiple
reports have proposed that p53 is a negative regulator of somatic cell reprogramming, and that elimination of
p53 increases iPSC reprogramming efficiency. However, basal p53 levels are elevated in ESC and iPSC
compared with somatic cells, leading us to propose an innovative hypothesis-that iPSC reprogramming is
incomplete due to insufficient inhibition of elevated p53 by p53 inhibitory factors. We further hypothesized
that A-iPSC may be unable to activate these putative p53 inhibitory factors to overcome the elevated p53
during iPSC reprogramming. As a result, p53 cannot be completely restrained, and the residual p53 activity
stimulates a constitutive DNA damage response that mimics what normally occurs only in response to a
genotoxic insult. A chronic DNA damage response (via p53-dependent and -independent pathways) has also
been observed during normal aging of somatic cells, and can lead to the complete loss of the DNA damage
response during cancer development. We posited that epigenetic destruction of the entire DNA damage
response would improve A-iPSC reprogramming and quality. In preliminary studies, we examined the function
of two putative p53 inhibitory factors and used these factors to identify pluripotent regulatory factors that can
correct the aging-related epigenetic landscape and improve the quality of A-iPSC. In this proposal, we will
examine the function of these pluripotent regulatory factors by conducting a comprehensive comparative
analysis of these iPSC types. In Aim 1, we will determine the mechanism by which the pluripotent regulatory
factors reverse the aberrant DNA damage response and negative effects of aging on the A-iPSC phenotype. In
Aim 2, we will determine the functional effects of the pluripotent regulatory factors by comparing the
pluripotency and differentiation potential of each cell line in several in vitro and in vivo tests. Ultimately, our
findings will provide critical insight into how we can improve the quality of patient-specific stem cells derived
from aged patients for use in tissue regeneration and transplantation.
Public Health Relevance
Regenerative medicine using individual patent-derived iPSC has enomous potential to generate
histocompatible transplantable tissue; this approach will particuarly benefit the aged population who is more
likely to have degenerative disease. Ultimately, our findings and proposed research will provide critical insight
into how we can improve the quality of patient-specific stem cells derived from aged patients for use in tissue
regeneration and transplantation.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
A new hypothesis: role of p53 inhibitory factors in cellular reprogramming
-
批准号:9268543
-
项目类别:
-
资助金额:$46.62万
-
财政年份:2014
-
负责人:Kitai Kim
-
依托单位:
A new hypothesis: role of p53 inhibitory factors in cellular reprogramming
-
批准号:9064044
-
项目类别:
-
资助金额:$46.62万
-
财政年份:2014
-
负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
-
批准号:8534806
-
项目类别:
-
资助金额:$23.27万
-
财政年份:2008
-
负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
-
批准号:7510675
-
项目类别:
-
资助金额:$8.94万
-
财政年份:2008
-
负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
-
批准号:8484937
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2008
-
负责人:Kitai Kim
-
依托单位:
国内基金
海外基金
登录
查看更多内容
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
-
批准号:JCZRLH202601523
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2026
-
负责人:
-
依托单位:
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
-
批准号:JCZRQN202500010
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:
-
依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
-
批准号:2025JJ70209
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:雷芬芳
-
依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
-
批准号:--
-
项目类别:面上项目
-
资助金额:--
-
批准年份:2024
-
负责人:万荣
-
依托单位:
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
-
批准号:2023JJ50274
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:贺志明
-
依托单位:
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
-
批准号:--
-
项目类别:地区科学基金项目
-
资助金额:33万元
-
批准年份:2022
-
负责人:都义日
-
依托单位:
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
-
批准号:--
-
项目类别:面上项目
-
资助金额:52万元
-
批准年份:2022
-
负责人:叶宝东
-
依托单位:
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:10.0万元
-
批准年份:2022
-
负责人:于海兵
-
依托单位:
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
-
批准号:81973577
-
项目类别:面上项目
-
资助金额:55.0万元
-
批准年份:2019
-
负责人:辛贵忠
-
依托单位:
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
-
批准号:81602908
-
项目类别:青年科学基金项目
-
资助金额:18.0万元
-
批准年份:2016
-
负责人:刘括
-
依托单位: