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)
淋巴管在组织液稳态和免疫监视中起重要作用。因此,在本发明中,
由于血管发育异常或淋巴管受损导致淋巴管功能受损
导致体液排出受阻并导致水肿的发展。尽管持续
水肿发生率增加,治疗选择仅限于保守治疗或姑息治疗
手术在过去的几十年里,新的生物治疗,如基因或细胞治疗已经出现,
治疗各种心血管疾病。然而,成体干细胞的作用被证明是最小的,
胚胎或诱导多能干细胞(ESC/iPSC)衍生的细胞的生产和维持成本高,
可能会引起副作用。为了避免这些问题,一种新的方法,称为直接重编程或直接
已经开发了转化,其中体细胞通过过表达转化为其它谱系细胞
谱系或细胞类型特异性转录因子(TF)。这种方法允许更简单和更安全的靶细胞
生成,并具有更方便的临床翻译的潜力。通过这种直接的重新编程
方法,我们已经成功地通过ETV 2产生了重编程内皮细胞(rEC),最近,
重编程淋巴管内皮细胞(rLEC)。
该项目的总体目标是开发一种直接重编程方法来治疗水肿。
用于治疗的直接EC重编程方法有两种选择:细胞治疗或直接体内重编程。
在本提案中,我们将采用这两种选择。对于临床应用,两者都需要更安全的递送载体,
使基因组整合的可能性最小化。因此,我们开发了腺病毒-ETV2(Ad-ETV2)载体。作为
第一种方法,我们将使用rLEC开发基于细胞的疗法。作为第二种方法,我们将开发一个
直接体内重编程方法,而不使用细胞。在后者中,将Ad-ETV2注射到动物体内,
模型来观察宿主细胞是否可以重新编程为LEC并形成新的淋巴管。到目前为止,
这两种方法都没有尝试用于治疗水肿。具体而言,在目标1中,我们
将通过改变各种培养条件从人成纤维细胞产生早期和晚期rLEC。在目标2中,
将确定rLEC对实验性水肿的治疗作用及其机制
这些治疗效果。在目标3中,我们将探索ETV 2是否能够直接将成纤维细胞重编程为
功能性LEC,诱导淋巴管形成,并改善水肿。我们预计,
提出的实验将产生新的见解的作用,新的细胞和基因治疗治疗,
水肿
项目成果
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