Lymphatic Regeneration by Direct Cellular Reprogramming
通过直接细胞重编程实现淋巴再生
基本信息
- 批准号:10744935
- 负责人:
- 金额:$ 52.09万
- 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:AddressAdenovirus VectorAnimal ModelBiologicalBiological Response Modifier TherapyBody FluidsBypassCardiovascular DiseasesCardiovascular systemCell LineageCell ReprogrammingCell TherapyCellsCharacteristicsClinicalDataDependenceDevelopmentDiseaseEmbryoEndothelial CellsExhibitsFibroblastsFluid BalanceGenerationsGenesGenomicsGoalsGrowthHistologicHumanImaging technologyImmunologic SurveillanceImpairmentIncidenceInsertion MutationLentivirus VectorLymphaticLymphatic Endothelial CellsLymphatic functionLymphedemaMagnetic Resonance ImagingMeasurementMethodsMolecularMorbidity - disease rateMusNatural regenerationNear-infrared optical imagingObstructionPalliative SurgeryPlayRegulationResearchResidual stateRoleSomatic CellTherapeuticTherapeutic EffectTissuesTransplantationTumorigenicityUndifferentiatedVariantViraladult stem cellcell typeclinical applicationclinical translationcostdelivery vehicleexperimental studygene therapyhuman embryonic stem cellhuman pluripotent stem cellin vivoinduced pluripotent stem cellinnovative technologiesinsightlymphatic developmentlymphatic vesselmortalityneovascularizationnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionparacrineprogramsregenerative therapyside effectstem cellssuccesstranscription factorvectorwound healing
项目摘要
Project Summary (Abstract)
Lymphatic vessels play an important role in tissue fluid homeostasis and immune surveillance. Thus,
impaired function of lymphatic vessels due to abnormal vessel development or damaged lymphatic vessels
causes obstruction of draining body fluid and leads to the development of lymphedema. Despite a continuous
increase in the incidence of lymphedema, therapeutic options are limited to conservative treatment or palliative
surgery. Over the past decades, new biological treatments such as gene or cell therapy have emerged for
treating various cardiovascular diseases. However, the effects of adult stem cells turned out to be minimal, and
embryonic or induced pluripotent stem cell (ESC/iPSC)-derived cells are costly to produce and maintain and
may cause side effects. To avoid these problems, a new approach, called direct reprogramming or direct
conversion has been developed, in which somatic cells are converted into other lineage cells by overexpression
of lineage- or cell-type specific transcription factors (TFs). This approach allows simpler and safer target cell
generation and has the potential for more convenient clinical translation. With this direct reprogramming
approach, we have successfully generated reprogrammed endothelial cells (rECs) via ETV2, and more recently,
reprogrammed lymphatic ECs (rLECs).
The overall goal of this project is to develop a direct reprogramming approach for treating lymphedema.
The direct EC reprogramming approach for therapy has two options: cell therapy or direct in vivo reprogramming.
In this proposal, we will follow both options. For clinical application, both require a safer delivery vector to
minimize the possibility of genomic integration. Thus, we developed an adenoviral-ETV2 (Ad-ETV2) vector. As
a first approach, we will develop a cell-based therapy using rLECs. As a second approach, we will develop a
direct in vivo reprogramming approach without using cells. In the latter, Ad-ETV2 will be injected into animal
models to see whether host cells can be reprogrammed into LECs and form new lymphatic vessels. To date,
none of these two approaches have been attempted for treating lymphedema. More specifically, in Aim 1, we
will generate early and late rLECs from human fibroblasts by changing various culture conditions. In Aim 2, we
will determine the therapeutic effects of rLECs on experimental lymphedema and the mechanisms underlying
these therapeutic effects. In Aim 3, we will explore whether ETV2 is able to directly reprogram fibroblasts into
functional LECs, induce lymphatic vessel formation, and ameliorate lymphedema. We anticipate that the results
of the proposed experiments will yield new insight into the role of novel cell and gene therapy for treating
lymphedema.
项目摘要(摘要)
项目成果
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