Regulation of Mesenchymal Stem Cell Secretome for Treatment of Microglia Damage in Traumatic Brain Injury
间充质干细胞分泌组的调节治疗创伤性脑损伤中的小胶质细胞损伤
基本信息
- 批准号:10626686
- 负责人:
- 金额:$ 53.9万
- 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:2022-08-03 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAgonistAlzheimer&aposs DiseaseAnti-Inflammatory AgentsAttentionAttenuatedBiologicalBiological Response Modifier TherapyBlindnessBrainCD44 geneCause of DeathCell TherapyChemistryClinicalCognitiveCommunicable DiseasesDataDiseaseDisease associated microgliaDoseEconomic BurdenEnvironmentEventGenerationsGenetic TranscriptionGoalsHealth SciencesHematologyHistologicImpaired cognitionInflammationInjuryKnowledgeLabelLaboratoriesLipopolysaccharidesMediatingMediator of activation proteinMesenchymalMesenchymal Stem CellsMessenger RNAMethodsMicrogliaModelingMolecularMolecular AnalysisMusNerve DegenerationNervous System TraumaNeurodegenerative DisordersOrganPathologyPhagocytosisPharmacologyPhenotypePre-Clinical ModelPrevalenceProcessProteinsPublic HealthPublishingRegulationResearchRetinaRoleRouteSafetySerumSignal PathwaySignal TransductionStromal CellsTBI treatmentTSG-6 proteinTYROBP geneTennesseeTestingTherapeuticTherapeutic EffectTissuesToxic effectTraumatic Brain InjuryUniversitiesVisionVisualVisual impairmentWorld Health Organizationcognitive functioncontrolled cortical impactdisabilityengineered exosomesexosomeexperiencefunctional outcomesgenetic approachimprovedimproved functioningin vivoindividualized medicineinhibitorinnovationknock-downneurovascularoverexpressionpreservationpublic health relevancereceptorregenerativeregenerative therapyresponsestemstem cell biologystem cell therapystem cells
项目摘要
ABSTRACT
The World Health Organization predicts that traumatic brain injury (TBI) will surpass many diseases, including
infectious diseases, as a significant cause of death and disabilities, including significant cognitive dysfunction
and visual impairment. Mesenchymal stem/stromal cell (MSC) therapies have gained considerable attention as
a strategy for protecting against neurodegenerative diseases. However, a poor understanding of the
mechanisms of therapeutic action has hampered their regulatory approval for clinical use. We have pioneered
the therapeutic application of adipose MSC-derived concentrated conditioned media (ASC-CCM), a "secretome"
containing soluble proteins and exosomes, for neurovascular pathologies across a range of preclinical models.
Guided by promising in vivo efficacy data and identification of TNF-Stimulated Gene-6 protein (TSG-6) as an
exosome-cargo protein that suppresses microglial activation, we now propose studies to determine if non-
invasive delivery of ASC-CCM protects against TBI-induced damage. We will test the central hypothesis that
TSG-6 enriched ASC-CCM ameliorates the generation of TBI-induced disease-associated microglia (DAM),
thereby modulating phagocytosis and inflammation to restore the microglial homeostatic state to protect visual
and cognitive function. In Aim 1, using a validated controlled cortical impact model of TBI (CCI-TBI) with and
without intranasal ASC-CCM treatment, we will a) establish the DAM phenotypic correlates of TBI-induced loss
of cognitive and visual functions and b) establish the efficacy of ASC-CCM treatment in TBI. In Aim 2, using
microglia in culture, we will determine if activation of the DAM signature through TYROBP-APOE4-axis signaling
leads to phagocytosis and inflammation and determine how exosomal TSG-6 modulates TYROBP-APOE4-
mediated DAM activation. In Aim 3, we will investigate the hypothesis that exosomes carrying TSG-6 protein are
sufficient to modulate the activation of DAM signature and thus impart the therapeutic benefit in TBI. We will
also study the distribution of exosomes in the tissues and study potential safety and toxicity. The proposed
research is significant and innovative because our expected results would provide the rationale for developing
mechanistically defined regenerative therapies tailored to modulating microglial phenotypes and signaling
pathways involved in neurodegeneration. The PI's laboratories have been engaged for nearly a decade in
developing regenerative and pharmacological therapies for neurotrauma and are well suited to conduct studies
proposed in this application. Our environment at the University of Tennessee Health Science Center and Diadem
Biotherapeutics, Inc makes us uniquely qualified to pursue this objective, given the extensive collective
experience in molecular and stem cell biology, exosome engineering, proinflammatory signaling networks, and
neurotrauma models.
摘要
项目成果
期刊论文数量(0)
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Rajashekhar Gangaraju其他文献
Rajashekhar Gangaraju的其他文献
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{{ truncateString('Rajashekhar Gangaraju', 18)}}的其他基金
Vascular and Neuronal Repair with Adipose Stromal cells in Retinopathy
脂肪基质细胞在视网膜病变中修复血管和神经元
- 批准号:
8503030 - 财政年份:2013
- 资助金额:
$ 53.9万 - 项目类别:
Vascular and Neuronal Repair with Adipose Stromal cells in Retinopathy
脂肪基质细胞在视网膜病变中修复血管和神经元
- 批准号:
8623134 - 财政年份:2013
- 资助金额:
$ 53.9万 - 项目类别:
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