Reprogramming Gene Regulatory Networks to a Hematopoietic Stem Cell State
将基因调控网络重编程为造血干细胞状态
基本信息
- 批准号:10716641
- 负责人:
- 金额:$ 52.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAutoimmune DiseasesBindingBloodBlood CellsBlood VesselsCell ReprogrammingCellsCharacteristicsChromatinClinicalDNA SequenceDataDevelopmentDiseaseEndothelial CellsEndotheliumEnhancersEpigenetic ProcessEventFOSB geneFrequenciesGFI1 geneGene Expression ProfileGenerationsGeneticGoalsGraft RejectionGrowthHematopoiesisHematopoieticHematopoietic NeoplasmsHematopoietic Stem Cell SpecificationHematopoietic Stem Cell TransplantationHematopoietic Stem Cell heterogeneityHematopoietic SystemHematopoietic stem cellsHomeostasisHomologous TransplantationIn VitroIndividualInjuryLinkMaintenanceMammalian CellMeasurementMediatingMolecularPatientsPersonsPhysiologicalPopulationProcessProductionRUNX1 geneRegulator GenesResearchRiskSPI1 geneSeminalSignal PathwaySignal TransductionSiteSomatic CellSourceSystemTherapeuticTissuesTransgenic MiceTransplantationUmbilical Cord BloodValidationcell typeclinically relevantcomparativecurative treatmentsendothelial stem cellexperimental studygene regulatory networkgraft vs host diseasehematopoietic stem cell expansionhematopoietic stem cell fatehemogenic endotheliumin vivoinsightintercellular communicationmouse modelmultiple omicsnovelnovel strategiespluripotencyprogramsreconstitutionstem cell genesstem cell populationstem cell therapytranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
Hematopoiesis is a continuous process of blood-cell production occurring through the orchestrated activity
of hematopoietic stem cells (HSCs). Although HSCs have tremendous clinical utility due to their ability to
reconstitute the hematopoietic system by transplantation, their benefit remains limited by the lack of matched
donors. Direct reprogramming of endothelial cells into HSCs via induction of reprogramming factors has recently
emerged as a promising alternative. The overall goal of our proposal is to reveal the molecular mechanisms by
which the reprogramming factors FOSB, GFI1, RUNX1, and SPI1 (FGRS) revert endothelial cells to functional
reprogrammed HSCs (reHSCs). Understanding the basis by which the genetic networks become rewired for this
profound cell type conversion will provide insights into diverse forms of reprogramming, development, and
disease. We discovered that early in the reprogramming process, FGRS directly coordinate two tasks: selection
and activation of multipotent HSC enhancers and disruption of endothelial enhancers and transcription factors
(TFs). We hypothesize that the effect of FGRS on endothelial TF binding is as crucial for reprogramming as the
activation of multipotency enhancers, and we propose to dissect the underlying molecular mechanisms for these
processes. Using single-cell multiomic (scRNA & ATAC-seq) profiling, we further discovered that in intermediate
reprogramming, the relatively homogenous starting endothelial cells are replaced by heterogeneous HSC
populations. How the transition from somatic (endothelial) to multipotent (HSC) regulatory programs occurs in
individual cells undergoing in vitro reprogramming remains unknown. To potentiate in vivo reprogramming, we
generated a novel transgenic mouse model that allows constant FGRS expression in all somatic tissues and
facilitates the recording of all key bifurcating events that lead to HSC establishment and maintenance. Based on
our studies, we propose to dissect the molecular and cellular mechanisms by which FGRS promote cell fate
changes in the context of endothelial-to-HSC reprogramming. In our first aim, we will uncover the molecular
mechanisms by which FGRS target and modulate endothelial and HSC gene regulatory networks. In the second
aim, we will delineate the intrinsic and extrinsic signaling pathways that promote endothelial-to-HSC
reprogramming. We expect that our program will yield fundamental insights into the control of mammalian cell
identity and may lead to novel strategies to generate therapeutically relevant HSCs with high efficiency.
项目总结/文摘
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 }}
Konstantinos Chronis其他文献
Konstantinos Chronis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('Konstantinos Chronis', 18)}}的其他基金
相似国自然基金
Autoimmune diseases therapies: variations on the microbiome in rheumatoid arthritis
- 批准号:31171277
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
相似海外基金
Autoantibodies and antibody-secreting cells in neurological autoimmune diseases: from biology to therapy
神经性自身免疫性疾病中的自身抗体和抗体分泌细胞:从生物学到治疗
- 批准号:
479128 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Operating Grants
Effects of maternal immune activation on autoimmune diseases in offsprings
母体免疫激活对后代自身免疫性疾病的影响
- 批准号:
23H02155 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
IPP: AUTOIMMUNE DISEASES STATISTICAL AND CLINICAL COORDINATING CENTER (ADSCCC)
IPP:自身免疫性疾病统计和临床协调中心 (ADSCCC)
- 批准号:
10788032 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Biomarkers of vascular endothelial dysfunction in systemic autoimmune diseases: analysis of circulating microRNAs
系统性自身免疫性疾病中血管内皮功能障碍的生物标志物:循环 microRNA 分析
- 批准号:
23K14742 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Structural mechanisms of autoimmune diseases targeting cys-loop receptors
针对半胱氨酸环受体的自身免疫性疾病的结构机制
- 批准号:
10864719 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Developing non-immunosuppressive immune-based therapeutics for targeted treatment of autoimmune diseases
开发非免疫抑制性免疫疗法来靶向治疗自身免疫性疾病
- 批准号:
10586562 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY
免疫治疗引起的自身免疫性疾病的新型体液和细胞生物标志物
- 批准号:
10593224 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Regulation of autoimmune diseases by PTPN22 phosphatase
PTPN22磷酸酶对自身免疫性疾病的调节
- 批准号:
23K06589 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Decipher and target GABA metabolism and GABA receptor-mediated signaling in autoimmune diseases
破译并靶向自身免疫性疾病中的 GABA 代谢和 GABA 受体介导的信号传导
- 批准号:
10623380 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别:
Targeting the long isoform of the prolactin receptor to treat autoimmune diseases and B-cell malignancies
靶向催乳素受体的长亚型来治疗自身免疫性疾病和 B 细胞恶性肿瘤
- 批准号:
10735148 - 财政年份:2023
- 资助金额:
$ 52.19万 - 项目类别: