Deciphering Mechanisms of Astrocyte-BBB Interaction in Normal and Ischemic Stroke
解读正常和缺血性中风中星形胶质细胞-BBB相互作用的机制
基本信息
- 批准号:10585849
- 负责人:
- 金额:$ 45.68万
- 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:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdultAnatomyAreaArginineAstrocytesBlood - brain barrier anatomyBlood VesselsBrainBrain InjuriesBrain regionCCL2 geneCause of DeathCell CommunicationCell physiologyCellsCerebral IschemiaConditioned Culture MediaCoupledDataDegenerative DisorderDiseaseEndothelial CellsEndotheliumExhibitsExtravasationGeneticGliosisGoalsHealthHomeostasisImpairmentIn VitroInfarctionIntercellular JunctionsIschemic StrokeKnowledgeMaintenanceMalignant NeoplasmsMediatingMetabolicMetabolismMolecularMorphologyMusNeurodevelopmental DisorderNeurogliaOxidesParacrine CommunicationPathogenesisPathologicPathway interactionsPatientsPhysiologicalPhysiologyPlayProductionPropertyRoleSignal PathwaySignal TransductionSodium-Bicarbonate SymportersStrokeTestingTimeTransgenic MiceVariantawakeblood-brain barrier disruptionblood-brain barrier functioncell typecentral nervous system injurychemokinecytokineextracellulargain of functionin vivoloss of functionmotor disordermouse modelmultiple omicsnervous system disordernovelpH Homeostasispost strokepreventresponsestroke patientstroke risk
项目摘要
SUMMARY AND ABSTRACT
Astrocytes are the most diverse glial cell type and maintain essential interactions with endothelial cells to form
the blood-brain barrier (BBB). The BBB plays a major role in CNS homeostatic function, while dysregulation of
the astrocytic BBB contributes to a spectrum of neurological disorders, ranging from neurodevelopmental and
degenerative diseases to CNS injury and malignancy. Particularly, pathologic astrocyte-BBB interactions
contribute to ischemic stroke, which is the 5th leading cause of death in the U.S. However, the mechanisms
underlying maintenance of BBB integrity, both in health and in diseases such as stroke, remain poorly defined.
The overarching goal of this proposal is to elucidate novel targets and associated signaling pathways influencing
normal astrocyte-BBB function and to leverage this knowledge to define key mechanisms for BBB disruption
after ischemic cerebral stroke. This proposal focuses on an astrocyte-enriched sodium-bicarbonate cotransporter
1, Slc4a4, which was previously identified as a glial-specific regulator of both intracellular and extracellular pH.
While pH homeostasis is essential for brain function and patients carrying Slc4a4 variants can suffer ischemic
stroke, a regulatory role of Slc4a4 in astrocyte-BBB integrity remains unknown. To begin addressing this
knowledge gap, we generated new transgenic mouse lines that temporally ablate Slc4a4 in astrocytes. Using this
genetic mouse model, we showed that loss of Slc4a4 significantly reduces astrocytic morphological complexity
and generates enlarged blood vessels with disrupted endothelial junctions. Our profiling analyses of astrocytic
Slc4a4-deficient mice and conditioned media of Slc4a4 ablated astrocytes revealed increased CCL2 production
and secretion coupled with dysregulated arginine-nitro oxide (NO) metabolism, further supporting a crucial role
for Slc4a4 in astrocyte-BBB integrity. Using an ischemic stroke mouse model, we found loss of Slc4a4 exacerbates
stroke-induced motor dysfunction and increases infarct area coupled with impaired reactive gliosis which results
in BBB disruption, which is rescued by inhibition of CCL2 in vivo. Based on these preliminary data, our central
hypothesis is that Slc4a4 functions to maintain astrocyte-BBB interactions and prevent progressive BBB leakage
in ischemic stroke, in part by inhibiting the chemokine CCL2. To address our hypothesis, we will first determine
how Slc4a4 regulates astrocyte morphology and physiology in the adult brain (Aim 1). Second, we will determine
the role of CCL2 in Slc4a4-dependent BBB maintenance in the adult brain (Aim 2). Upon completion, these
studies will establish whether and how Slc4a4-deficient astrocytes influence anatomical and physiological
properties of astrocytes, and will elucidate how Slc4a4 regulates astrocytic modulation of endothelial cell and
BBB integrity via NO metabolism that drive astrocytic CCL2 signaling in the adult brain. Lastly, we will define
the Slc4a4 pathway in the maintenance of BBB integrity following ischemic stroke (Aim 3). Together, elucidating
the Slc4a4 pathway could reveal fundamental mechanisms controlling astrocyte morphology, physiology, and
secreted molecules, and it will advance our understanding of astrocyte-BBB interactions after stroke.
摘要与摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hyun Kyoung Lee其他文献
Hyun Kyoung Lee的其他文献
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{{ truncateString('Hyun Kyoung Lee', 18)}}的其他基金
Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury
破译少突胶质细胞发育和白质损伤中的 Daam2-VHL 信号轴
- 批准号:
10556388 - 财政年份:2019
- 资助金额:
$ 45.68万 - 项目类别:
Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury
破译少突胶质细胞发育和白质损伤中的 Daam2-VHL 信号轴
- 批准号:
10338107 - 财政年份:2019
- 资助金额:
$ 45.68万 - 项目类别:
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