Investigating thrombocytopenia absent radius syndrome during primitive and definitive hematopoiesis using an induced pluripotent stem cell model
使用诱导多能干细胞模型研究原始造血和确定性造血过程中无桡骨综合征的血小板减少症
基本信息
- 批准号:10802107
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectAgonistAllelesApoptosisApoptoticAxonBiological AssayBiologyBloodBlood CellsBlood PlateletsBlood specimenCell CycleCell Cycle ArrestCell Cycle ProgressionCell Cycle RegulationCell DeathCell LineCell LineageCell ProliferationCell physiologyCellsCessation of lifeCharacteristicsComplexCongenital DisordersDefectDevelopmentDisease modelEmbryoErythroidEtiologyExhibitsFeedbackFlow CytometryGenerationsGenesGeneticHematological DiseaseHematopoiesisHematopoieticHematopoietic stem cellsHumanImpairmentIn VitroKnockout MiceLifeMegakaryocytesMegakaryocytopoiesesMessenger RNAMitoticModelingMutationMyelogenousOrganismPathogenesisPathway interactionsPatientsPatternPenetrancePhenotypePlatelet Count measurementPloidiesPolyploid CellsPopulationPredispositionProcessProliferatingProteinsRNARNA ProcessingRNA SplicingRadialRegulationRoleSamplingSingle Nucleotide PolymorphismSpecificitySurfaceSyndromeSystemTP53 geneTestingTherapeuticThrombocytopeniaTissue-Specific Gene ExpressionTissuesUmbilical Cord BloodUntranslated RNAValidationYolk Saccell typedisease phenotypeexperimental studygene correctionhuman diseaseimprovedin vitro Modelin vivoinduced pluripotent stem cellinsightmRNA Expressionmouse modelnovelpostnatalprematureprogenitorprogramspromoterresponseskeletalsmall hairpin RNAstem cell modelstem cellstranscriptome sequencing
项目摘要
Thrombocytopenia absent radius (TAR) syndrome is a rare congenital disorder that causes absence of
the radii, reduced numbers of mature megakaryocytes (MKs), and thrombocytopenia. TAR is caused by
mutations in the RBMBA gene, resulting in reduced mRNA expression of RBMBA and levels of its encoded
protein, Y14, in patient platelets. Since Y14 has no known roles in MK biology, it is currently not understood
how deficiencies in this protein contributes to a MK phenotype without affecting other hematopoietic lineages.
Previous studies of Y14 depletion have identified a role for Y14 in apoptosis and cell cycle regulation, but it is
unclear whether this is the mechanism responsible. Both the postnatal emergence of the thrombocytopenia in
TAR and the known differences in MKs derived from primitive or definitive progenitor cells suggest that
definitive MKs may present a more severe phenotype and thus be a more insightful model. By modeling this
disease in vitro using patient-derived induced pluripotent stem cells (iPSCs) and isogenic corrected lines, we
can assess the effects of TAR on pure cell populations to observe lineage- and developmental stage-specific
changes without influence from the compensatory feedback mechanisms that regulate blood cell generation in
vivo. Overall, we hypothesize that Y14 depletion in TAR syndrome impairs maturation of definitive MKs more
severely than primitive MKs through altered cell cycle and apoptosis regulation, and it does not affect the
development of other blood lineages. Aim 1 of this proposal will determine the specific characteristics of MKs
that is altered due to Y14 depletion during primitive and definitive differentiation. Aim 1A will evaluate aspects
of MK maturation and functionality to determine the specific MK phenotype, and Aim 1 B will determine if
reduced Y14 alters apoptosis and cell cycle progression in MKs as a potential mechanism for this phenotype.
Using RNA-seq, we will detect differential expression of genes related to these pathways or identify any novel
targets with the potential to contribute to the MK defect. Aim 2 will address the MK specificity of TAR by
comparing consequences of Y14 depletion in MK differentiation to erythroid and myeloid differentiations. Aim
2A will discern whether the hematopoietic lineages regulate Y14 RNA or protein levels differently. Aim 28 will
use cell proliferation and lineage-specific surface marker expression to detect potential defects in erythroid or
myeloid development. We will also determine whether cell cycle and apoptosis regulation are altered in these
other lineages as well as any additional pathways that are identified in Aim 1 B. This will be the first study to
directly compare the regulation of cell cycle, apoptosis, and MK maturation during primitive and definitive
hematopoiesis and test whether these models have the potential for divergent disease phenotypes. The results
of this study will not only elucidate the mechanism of TAR syndrome in MKs, but its insight into MK biology at
different stages of development will have important implications for improving current in vitro disease models
and tailoring therapeutics to distinct tissue systems to reduce human disease.
桡骨缺失性血小板减少症(TAR)综合征是一种罕见的先天性疾病,导致桡骨缺失
项目成果
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{{ truncateString('Catriana Nations', 18)}}的其他基金
Investigating thrombocytopenia absent radius syndrome during primitive and definitive hematopoiesis using an induced pluripotent stem cell model
使用诱导多能干细胞模型研究原始造血和确定性造血过程中无桡骨综合征的血小板减少症
- 批准号:
10535333 - 财政年份:2022
- 资助金额:
$ 4.77万 - 项目类别:
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