Transcriptional and Epigenetic Control of Pluripotency and Self-Renewal by Honey Bee Royalactin and its human structural analog
蜜蜂 Royalactin 及其人类结构类似物对多能性和自我更新的转录和表观遗传控制
基本信息
- 批准号:10417198
- 负责人:
- 金额:$ 39.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAutomobile DrivingBackBeesBindingBiological AssayBiologyCell MaintenanceCell Surface ReceptorsCell surfaceCellsCellular AssayChromatinComplexCongenital AbnormalityDataDegenerative DisorderDerivation procedureDevelopmentDevelopmental ProcessDiabetes MellitusDiseaseDisease modelEmbryoEmbryologyEmbryonic DevelopmentEpigenetic ProcessEventGene ExpressionGene FamilyGeneticGenetic TranscriptionGoalsGrowth FactorHeterogeneityHoneyHumanHuman DevelopmentImpairmentLeadLigandsMaintenanceMalignant NeoplasmsMammalian CellMammalsMediatingMembraneMethodsMissionModelingMolecularMusNaturePhenotypePluripotent Stem CellsProteinsProteomicsPublic HealthReceptor Mediated Signal TransductionRegenerative MedicineRegulator GenesSignal PathwaySignal TransductionStem Cell FactorStem cell pluripotencyStimulusStudy modelsTherapeuticTransposaseUnited States National Institutes of HealthWorkanalogbaseblastomere structurecell behaviordevelopmental diseaseembryonic stem cellepigenetic regulationepigenomeepigenomicsflexibilityforward geneticsgene regulatory networkgenome-wide analysishuman diseasehuman embryonic stem cellimplantationimprovedimproved outcomeinsightloss of functionnovelnovel strategiespluripotencypluripotency factorpreservationreceptorregenerativeregenerative cellregenerative therapyresponseself-renewalsingle cell analysisstemstem cell biologystem cell differentiationstem cell fatestem cell self renewalstem cellsstemnesstissue repairtranscriptometranscriptome sequencingtranscriptomicswhole genome
项目摘要
Limitations in current treatment options for many congenital and acquired diseases in humans, including
birth defects, cancer, degenerative disorders and diabetes, highlight the need for the development of novel
approaches for regenerative medicine to dramatically improve tissue repair. The pluripotent nature of mammalian
embryonic stem cells (ESCs) makes them a convenient model for studying aspects of early development and
an invaluable starting point for deriving numerous therapeutically relevant cells for regenerative medicine.
Despite the remarkable progress made in deciphering mechanisms driving ESC pluripotency, fundamental gaps
remain in understanding how human embryonic stem cells (hESCs) regulate the pluripotent state. If we are to
use hESCs as a high-fidelity model for embryonic development, and if we wish to improve outcomes of hESC
differentiation and the fidelity of cellular reprogramming to pluripotency, then it is imperative that we understand
how hESCs fit into the paradigm of mammalian embryonic development. In this project we seek to answer some
of these fundamental questions, by characterizing and validating a potential alternative pluripotency state. Our
paradigm-shifting hypothesis stems from our unexpected discovery that the honey bee queen-maker protein,
Royalactin, and its structural analog in mammals, Regina, have unexpected robust pluripotency maintenance
effects in mammalian stem cells. We hypothesize that Regina/Royalactin stabilize and capture a pivotal
pluripotent state distinct from the existing pre- (naïve) and post- (primed) implantation associated stem cell states.
I outline here a plan to molecularly characterize this novel cellular metastable state with 3 specific aims. In Aim
1, we will Isolate and characterize the composition and activity of the receptor complex(es) in ESCs. We
hypothesize that Regina/Royalactin, as secreted molecules, likely directly interact with a receptor partner on the
membrane of responsive cells to affect gene expression and subsequent cellular behavior. We will identify the
receptor(s) through multiple high throughput forward genetics and proteomic strategies. In Aim 2, we will derive
and maintain murine and human ESCs to functionally demonstrate that the Regina/Royalactin-mediated state of
pluripotency can be related back to the signaling pathways involved in lineage specification and maintenance in
the embryo itself. Establishment of a new distinct stage of mammalian pluripotency will be an important advance
in our understanding of early lineage commitment. Lastly, in Aim 3 we will elucidate and characterize the critical
mechanisms that interface between Regina/Royalactin and downstream epigenetic and transcriptomic events.
The genome-wide analyses will be compared to current established conditions to determine whether genetic and
epigenetic instability of the ESCs, associated with impaired developmental potential, exists. Taken together, our
data will directly establish how a novel endogenous mammalian pluripotency factor instigates fate decisions in
ESCs, and provide a new platform to study the principles governing cell potency, epigenetic regulation, and the
mechanisms that regulate developmental processes in naïve pluripotent stem cells.
目前人类许多先天性和获得性疾病的治疗方案存在局限性,包括
项目成果
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Kevin Chun-Kai Wang其他文献
Kevin Chun-Kai Wang的其他文献
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{{ truncateString('Kevin Chun-Kai Wang', 18)}}的其他基金
Transcriptional and Epigenetic Control of Pluripotency and Self-Renewal by Honey Bee Royalactin and its human structural analog
蜜蜂 Royalactin 及其人类结构类似物对多能性和自我更新的转录和表观遗传控制
- 批准号:
10237127 - 财政年份:2020
- 资助金额:
$ 39.55万 - 项目类别:
Transcriptional and Epigenetic Control of Pluripotency and Self-Renewal by Honey Bee Royalactin and its human structural analog
蜜蜂 Royalactin 及其人类结构类似物对多能性和自我更新的转录和表观遗传控制
- 批准号:
10646468 - 财政年份:2020
- 资助金额:
$ 39.55万 - 项目类别:
Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis
通过操纵特应性皮炎先天免疫的非编码RNA调节炎症细胞因子的靶向治疗调节
- 批准号:
10021394 - 财政年份:2019
- 资助金额:
$ 39.55万 - 项目类别:
Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis
通过操纵特应性皮炎先天免疫的非编码RNA调节炎症细胞因子的靶向治疗调节
- 批准号:
9912493 - 财政年份:2019
- 资助金额:
$ 39.55万 - 项目类别:
Transcriptional regulation of chromatin modifying complexes by noncoding RNAs
非编码RNA对染色质修饰复合物的转录调控
- 批准号:
8306126 - 财政年份:2011
- 资助金额:
$ 39.55万 - 项目类别:
Transcriptional regulation of chromatin modifying complexes by noncoding RNAs
非编码RNA对染色质修饰复合物的转录调控
- 批准号:
8165143 - 财政年份:2011
- 资助金额:
$ 39.55万 - 项目类别:
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