Targeted Mitochondrial Delivery Systems for Vascular Interventions
用于血管干预的靶向线粒体输送系统
基本信息
- 批准号:10905155
- 负责人:
- 金额:$ 50.29万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAffectAgingAneurysmAnti-Inflammatory AgentsAntioxidantsAortaApoptosisApoptoticAtherosclerosisBindingBiocompatible MaterialsBiogenesisBlood VesselsCardiovascular DiseasesCellsCellular Metabolic ProcessClinicalDevelopmentDevicesDiabetes MellitusDiseaseEncapsulatedEndothelial CellsEndotheliumEngineeringExtracellular MatrixGoalsHomeostasisHydrogelsIn VitroInflammationInflammatoryInterventionIschemic StrokeMacrophageMacrophage ActivationMatrix MetalloproteinasesMesenchymal Stem CellsMitochondriaModelingMyocardial InfarctionNerve DegenerationPathogenesisPathologyPatientsPenetrationPeptidesPharmacological TreatmentPhenotypeProductionPropertyPublic HealthRattusReactive Oxygen SpeciesResearchRoleSeriesSignal TransductionSmooth Muscle MyocytesSourceSpecificityStentsStressSystemTechnologyTherapeuticTissuesTransplantationTunica AdventitiaValidationVascular DiseasesVascular Smooth MuscleVascular SystemWorkcalcificationcell typeclinical applicationclinical translationdelivery vehicledesignefficacious treatmentendothelial dysfunctionfunctional restorationimplantationimprovedin vivoinjuredinnovationintercellular connectionmicrovesiclesmitochondrial dysfunctionmouse modelnovel strategiesoxidative damagepreclinical studypreservationrepairedstem cellstargeted deliverytherapy outcometooltranslational barrieruptakevascular inflammation
项目摘要
PROJECT SUMMARY
Mitochondrial dysfunction is a significant contributing factor in many common disorders, yet no pharmacological
treatment is currently available to restore mitochondrial function. An emerging therapeutic strategy is intercellular
mitochondrial transfer, where healthy mitochondria from a donor cell source can be transported to the stressed
recipient cells to achieve functional restoration. However, this strategy is currently hindered by several significant
technological challenges, including the lack of cell/tissue specificity, low cell internalization rate, and loss of
mitochondria function during delivery. Therefore, engineering targeted delivery systems to facilitate cell-specific
internalization with functional preservation is important for the clinical adaptation of the technology. The long-
term goal is to develop mitochondria-based therapeutics for common diseases in which mitochondrial
dysfunction is a prominent feature. The objective of this project is to develop advanced Mitochondrial Delivery
Systems (MDS) with high specificity, high efficiency, and functional preservation to enable control over the
quantity and quality of the transferred mitochondria. To achieve this goal, rational biomaterial design will be
utilized to enable the efficient delivery of mitochondria in three types of configurations, each designed to account
for differences in tissue accessibility and target-cell properties in the vascular system. Specifically, an
intravascular MDS will be developed to target dysfunctional endothelium (Aim 1), an endovascular MDS will be
developed to target apoptotic vascular smooth muscle cells (Aim 2), and a perivascular MDS will be developed
to target proinflammatory macrophages (Aim 3). The MDS will be engineered to achieve localization and
internalization to the target cell types, with functional preservation for mitochondria as the cargo for delivery. The
MDS will be firstly optimized for each of the target cell types in vitro, followed by validation of the delivery
technology and therapeutic potential in vivo. Through this work, we are expected to establish several clinical
applicable delivery tools that can effectively deliver functional mitochondria to diseased tissues. This study will
also provide key technological advancements toward developing mitochondria-based therapeutics for vascular
interventions, which may significantly expand the therapeutic options for various cardiovascular disease patients.
This technology will be designed to be modifiable/customizable for other diseases and cell types where
mitochondrial dysfunction is involved, thus leading to a series of innovative devices and therapeutics for more
efficacious treatments for many common pathologies involving dysfunctional mitochondria.
项目总结
线粒体功能障碍是许多常见疾病的一个重要因素,但没有药物作用
目前,恢复线粒体功能的治疗是可用的。一种新兴的治疗策略是细胞间
线粒体转移,在这种情况下,来自供体细胞来源的健康线粒体可以被运输到应激
以实现受体细胞的功能恢复。然而,这一战略目前受到以下几个重大问题的阻碍
技术挑战,包括缺乏细胞/组织特异性,细胞内化率低,以及
线粒体在分娩过程中发挥作用。因此,设计靶向递送系统以促进细胞特异性
保留功能的内化对于该技术的临床适应是重要的。长的-
学期目标是开发基于线粒体的治疗常见疾病的方法,其中线粒体
功能障碍是一个突出的特征。这个项目的目标是发展先进的线粒体传递。
具有高特异性、高效率和功能保留的系统(MDS),以实现对
转移的线粒体的数量和质量。为了实现这一目标,合理的生物材料设计将是
用于在三种类型的配置中实现线粒体的高效传递,每种配置都被设计为
以了解血管系统中组织可及性和靶细胞属性的差异。具体地说,一个
血管内MDS将以功能障碍的内皮为靶点(目标1),血管内MDS将被开发为
开发靶向凋亡的血管平滑肌细胞(目标2),并将开发血管周围MDS
以促炎症巨噬细胞为靶点(目标3)。MDS的设计将实现本地化和
内化到靶细胞类型,并将线粒体作为运送的货物进行功能保存。这个
MDS将首先在体外针对每种目标细胞类型进行优化,然后验证交付
体内的技术和治疗潜力。通过这项工作,我们有望建立几个临床
适用的输送工具,可以有效地将功能性线粒体输送到病变组织。这项研究将
还提供了开发基于线粒体的血管疗法的关键技术进步
干预措施,这可能极大地扩大各种心血管疾病患者的治疗选择。
这项技术将被设计为可针对其他疾病和细胞类型进行修改/定制
涉及线粒体功能障碍,从而导致了一系列创新设备和治疗方法
对许多涉及线粒体功能障碍的常见病理疾病的有效治疗。
项目成果
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