Direct chemical control of the hematopoietic master transcription factor PU.1
造血主转录因子 PU.1 的直接化学控制
基本信息
- 批准号:10540346
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Myelocytic LeukemiaAddressAffinityAreaBacteriophagesBindingBiologicalBiophysicsBloodBlood CellsCRISPR/Cas technologyCell NucleusCellsChemicalsClinicClinicalCollaborationsComplexDNADNA BindingDataDevelopmentDiseaseDrug TargetingETS Family ProteinEventExerciseFamilyFibrosisGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGenomicsGoalsHematopoiesisHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsHodgkin DiseaseHomeostasisHourHydration statusIRF4 geneInterferonsInvestigationKidney DiseasesLaboratory StudyLesionLibrariesLigandsLiver FibrosisLiver diseasesLung diseasesLymphoidLymphomaMalignant NeoplasmsMapsMediatingMetabolicMethodsModelingMolecularMolecular Mechanisms of ActionMultiple MyelomaMusMyelogenousMyeloid CellsNew AgentsNuclear ReceptorsOsmosisOsmotic PressurePathway interactionsPatientsPeptidesPhage DisplayPharmaceutical ChemistryPharmacologyPhenotypeProcessPropertyProteinsPulmonary FibrosisRNA InterferenceReagentResearchRoleSelection CriteriaSiteSourceSpecific qualifier valueSpecificitySteroidsStructural ModelsStructureSurfaceTechniquesTherapeuticTissuesToxic effectTranscriptional RegulationTransgenesTranslatingTranslationsVariantViralWaterWorkbasecofactorcytotoxicitydisease phenotypedrug discoverygenetic manipulationgenotoxicityimprovedinnovationinsightinterestkidney fibrosisleukemiamembernon-viral gene deliverynovelnovel therapeuticspharmacologicprogramsproto-oncogene protein Spi-1recruitscreeningstem cell homeostasissuccesstooltranscription factorviral gene delivery
项目摘要
PROJECT SUMMARY/ABSTRACT: Direct control of the hematopoietic master transcription factor PU.1
Hematopoiesis, the process by which all lineages of blood cells are derived, is under coordinate control by a
restricted group of transcription factors. Currently, factor-specific control relies heavily on genetic methods, such
as RNA interference and CRISPR/Cas9, to alter the expression of transcription factors of interest. While highly
selective, gene-based approaches are associated with significant latency (many hours to days) and therefore
cannot access critical cellular dynamics at timescales in the minute-to-hour régime. Moreover, cytotoxicity and
genotoxicity due to viral and non-viral gene delivery remain outstanding issues, particularly in therapy. Direct
chemical control of specific transcription factors could address these opportunities, but a general lack of
endogenous ligands for medicinal chemistry and broad structural homology challenge drug discovery. To meet
this challenge, we have translated the disposition of molecular hydration in factor/DNA recognition into an
orthogonal selection criterion to library screening. As proof of concept, we developed an osmotically driven phage
display screen to obtain short peptides that enhance or inhibit DNA binding by PU.1, a master transcription factor
in hematopoietic stem cell homeostasis and differentiation. De-regulation of PU.1 represents a major molecular
lesion in several hematopoietic malignancies (e.g., acute myeloid leukemia, multiple myeloma, and Hodgkin's
disease) as well as fibrosis of the lungs, liver, and kidneys. The objectives of this proposal are: to validate the
biological and molecular properties of PU.1-targeted peptides, and adapting the osmotic screening technique to
target other transcription factors that function in concert with PU.1. To achieve these objectives, we propose
three specific aims. 1) We will define the functional profiles of PU.1-targeted peptides in cultured hematopoietic
models, as well as primary murine and patient-derived leukemic and pro-fibrotic cells. Preliminary data show that
PU.1-targeted peptides enter the cell nucleus and modulate the expression of major PU.1 target genes in as
little as 30 min, an onset well below currently achievable limits by genetic manipulations. Our proposed studies
are aimed at characterizing their transcriptional profiles and the attendant changes in cellular and disease
phenotypes. 2) We will determine the molecular properties of peptide modulation of factor/DNA recognition.
Detailed studies are aimed at dissecting the diverse structural and mechanistic bases of peptide/complex
interactions. 3) We will expand osmotic screening to target lineage-specific transcription factors that co-regulate
with PU.1, including the interferon regulatory factors IRF4 and IRF8 that bind DNA cooperatively with PU.1, as
well as partners such as C/EBPα that are recruited collaboratively by low-affinity PU.1 binding. In summary, this
proposal is expected to advance transcription factor pharmacology with novel targeted reagents, particularly
activators, and demonstrate the combination of structural and physicochemical interrogation (library panning +
osmotic pressure) as a tractable, generalizable solution to overcome current bottlenecks in chemical control.
项目摘要/摘要:直接调控造血主转录因子PU.1
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 }}
Gregory Man Kai Poon其他文献
Gregory Man Kai Poon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('Gregory Man Kai Poon', 18)}}的其他基金
Direct chemical control of the hematopoietic master transcription factor PU.1
造血主转录因子 PU.1 的直接化学控制
- 批准号:
10322390 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
Direct activation of hematopoietic transcription factors
直接激活造血转录因子
- 批准号:
8947574 - 财政年份:2015
- 资助金额:
$ 39万 - 项目类别:
Osmotic responsiveness of the master immune regulator PU.1
主免疫调节剂 PU.1 的渗透反应性
- 批准号:
8770311 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
相似海外基金
Computing analysis of leukemic stem cell dynamics in acute myelocytic leukemia
急性粒细胞白血病白血病干细胞动力学的计算分析
- 批准号:
19K08356 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of immunotoxins with super-targeting mAb in the acute myelocytic leukemia
在急性髓细胞白血病中使用超靶向单克隆抗体产生免疫毒素
- 批准号:
23501309 - 财政年份:2011
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556971 - 财政年份:1980
- 资助金额:
$ 39万 - 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556968 - 财政年份:1980
- 资助金额:
$ 39万 - 项目类别:
ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
通过 MAB 疗法根除急性粒细胞白血病细胞
- 批准号:
3889304 - 财政年份:
- 资助金额:
$ 39万 - 项目类别:














{{item.name}}会员




