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
项目总结/文摘
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.
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A new hypothesis: role of p53 inhibitory factors in cellular reprogramming
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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
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批准号:9064044
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项目类别:
-
资助金额:$46.62万
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财政年份:2014
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负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
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批准号:7510675
-
项目类别:
-
资助金额:$8.94万
-
财政年份:2008
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负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
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批准号:8534806
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项目类别:
-
资助金额:$23.27万
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财政年份:2008
-
负责人:Kitai Kim
-
依托单位:
Hematopoietic potential of histocompatible embryonic stem cell lines
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批准号:8484937
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项目类别:
-
资助金额:$24.9万
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财政年份:2008
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负责人:Kitai Kim
-
依托单位:
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