Dysregulated cholesterol metabolism in Alzheimer's Disease astrocytes: Investigating contributions to neuronal dysfunction
阿尔茨海默病星形胶质细胞中胆固醇代谢失调:研究对神经元功能障碍的影响
基本信息
- 批准号:10755162
- 负责人:
- 金额:$ 4.16万
- 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 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptionAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAmericanApolipoproteinsAstrocytesBehavioralBioinformaticsBiologicalBiological AssayBiologyBlood VesselsBrainCause of DeathCell CommunicationCellsCholesterolCholesterol HomeostasisCommunicationCytokine SignalingDataData SetDatabasesDementiaDevelopmentDiagnosisDiseaseDoctor of PhilosophyEnvironmentExhibitsExperimental DesignsExposure toExtracellular MatrixFunctional disorderGenerationsGenesGoalsHealthHomeostasisImpairmentIn VitroIndividualInflammationInflammatoryLaboratoriesLifeLipidsLipoproteinsMeasuresMembraneMetabolicMetabolic PathwayMetabolismMultiomic DataNerve DegenerationNeuritesNeurodegenerative DisordersNeurogliaNeuronal DysfunctionNeuronsNeurosciencesOutcomePathologyPathway interactionsPatientsPhasePhenotypePhysiologicalPlayPostdoctoral FellowPrincipal InvestigatorPropertyProteomeRegulationResearchResearch PersonnelResearch Project GrantsRoleSignal TransductionSignaling MoleculeSourceSynapsesSynaptic TransmissionSystemTechnical ExpertiseTechniquesTrainingTransgenic MiceTransgenic ModelUnited StatesViralWild Type Mouseage related neurodegenerationcandidate identificationcareercell typecomparison controleffective therapyexperimental studyglobal healthhuman stem cellsin vivoin vivo Modelinduced pluripotent stem cellknock-downlipid metabolismlipid transportmetabolomicsmouse modelmulti-electrode arraysmultiple omicsneuron lossneurotoxicnoveloverexpressionpost-doctoral trainingpostsynapticpresynapticpreventresponseskillsstable isotopestem cell modelsynaptogenesistraffickingtranscriptomeuptake
项目摘要
Project Summary
The absence of effective therapies to slow or prevent progression have made Alzheimer’s Disease (AD)
a global health crisis. Inflammation, neuronal dysfunction, and eventual neuronal loss are hallmarks of AD.
Cholesterol metabolism is also implicated in AD and other neurodegenerative diseases. For example,
accumulation of lipid droplets that store intracellular lipids are observed in AD brains. Cholesterol acts as a
signaling molecules and is an essential component of biological membranes. Notably, cholesterol levels in the
presynaptic and postsynaptic compartments influence synaptic transmission. Thus, changes to cholesterol
metabolism could directly induce neuronal dysfunction and other AD-associated pathology.
While most research focuses on neurons, non-neuronal glial cells are essential in regulating neuronal
function and maintaining brain homeostasis. Astrocytes are a class of glial cell that interact with synapses, blood
vessels, and other glial cells, playing essential roles in the regulation of synaptic connectivity and function
throughout life. Recent studies suggest that changes to astrocytes are potential drivers of AD pathology.
Astrocytes have decreased physiological functions and release inflammatory factors in disease states. As the
main producers of cholesterol in the brain, cholesterol dysregulations in AD could also be primarily driven by
changes in astrocyte metabolism. However, it is still unclear to what extent cholesterol metabolism is
dysregulated in AD astrocytes and what specific genes could be targeted to reverse these changes.
The overall goal of my dissertation and post-doctoral research is to characterize cholesterol metabolism
in astrocytes in the context of AD. Preliminary data in Aim 1 demonstrates my ability to use human stem cell
models to study intrinsic changes in astrocytes derived from individuals with AD using multi-omic and
metabolomic approaches. In Aim 1, I propose taking a closer look at how cholesterol is dysregulated in AD
astrocytes and how these dysregulations promote AD-related astrocyte dysfunctions, such as adoption of
neurotoxic properties and loss of the ability to support neurons. During the K00 Phase, I propose expanding
these analyses to in vivo models to probe system-wide contributions of astrocyte cholesterol metabolism.
The Training Plan integrates scientific and professional development activities that will advance my long-
term career goals of becoming an independent neuroscience researcher and principal investigator of an
academic laboratory. The proposed research provides ample opportunities for developing technical expertise in
astrocyte biology, metabolism, and analytical techniques. My Sponsors will be instrumental in helping me build
skills in experimental design, scientific communication, and grantsmanship. They will also guide me in finding a
postdoctoral training environment that aligns with my long-term research and career goals.
项目总结
项目成果
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