Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
基本信息
- 批准号:10121379
- 负责人:
- 金额:$ 32.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAffectAlzheimer&aposs disease related dementiaAttentionAwardBehaviorBiological AssayBiosensorC9ORF72CRISPR/Cas technologyCatabolismCell SurvivalCell modelCellsChargeClinicalDataDementiaDiseaseDisease ProgressionEquilibriumFamilyFundingFunding OpportunitiesFutureGene MutationHumanHydrolaseImageImpairmentIndividualKymographyLongitudinal StudiesLysosomesMalignant NeoplasmsMeasurementMeasuresMetabolicMicroscopyModelingMorphologyMutationNeoplasm MetastasisNerve DegenerationNeurodegenerative DisordersNeuroepithelial CellsNeuronsNormal tissue morphologyNutrientOncogenicOrganellesOutcomeOutcome StudyPGRN genePathologyPatientsPharmacologyPresynaptic TerminalsProteinsProteolysisQuality ControlReagentReporterReportingRoleSomatic MutationSpecificityStainsStructure of retinal pigment epitheliumSwellingTestingTherapeuticTimeTissuesWorkbiomass fuelcancer cellcell behaviorcell motilitycellular engineeringgenetic approachinduced pluripotent stem celllongitudinal analysisloss of functionmacromoleculemisfolded proteinmutation carrierneuron lossneurotoxicnovel strategiesnovel therapeutic interventionparent grantpresenilin-1protein aggregationratiometricsensortime usetooltraffickingtumorigenic
项目摘要
Abstract
Cancers and Alzheimer’s Disease Related Dementias (ADRDs) are increasingly recognized as diseases with
dysregulated lysosomes. Although lysosome functions are critically dependent on a lumenal acidic pH of ~ 5.0
for the activity of contained acid-activated hydrolases, whether lysosome pH (pHlys) is dysregulated and a
determinant for impaired lysosome functions in cancers and ADRDs has received limited attention. With support
from our parent grant CA197856 on intracellular pH dynamics and cancer we generated and validated a new
genetically encoded pHlys biosensor, pHLARE (pH Lysosomal Activity REporter), which is the only pHlys sensor
that can be propagated in cells for longitudinal studies. We used pHLARE to show a significantly lower pHlys in
human cancer cells from different tissue origins and with different mutational signatures compared with tissue-
matched untransformed cells, and to identify new pharmacological and genetic approaches to experimentally
change pHlys. With funding from our parent grant we are using these new approaches to determine how
decreased pHlys enables cancer cell behaviors. Our supplement will use these new approaches developed
through our parent grant to address unresolved questions on pHlys in ADRDs, and hence, is ideally suited for
NOT-CA-20-019 funding. Our supplement tests the hypothesis that ADRDs have increased pHlys, which
decreases the activity of lumenal hydrolases and macromolecular catabolism, leading to increased
protein aggregation and neurodegeneration. In Aim 1 we will quantify pHlys in ADRD models expressing
pHLARE, including neuroepithelial cells engineered for loss of progranulin and presenilin 1, which are
determinants in ADRDs and associated with impaired lysosome function, and neurons differentiated from
NHCDR-generated iPSCs derived from patients with identified ADRDs and from unaffected family mutations
carriers and non-carriers. In Aim 2 we will determine functional consequences of dysregulated pHlys in ADRD
cell models by using pharmacological and genetic approaches we identified in studies in our parent grant that
change pHlys. Using the ADRD-associated cell models described in Aim 1 we will to determine the role of pHlys
dynamics in protein aggregation, a hallmark of ADRDs, as well as neuronal morphology and lysosome
localization and mobility, which are impaired in ADRDs resulting in lysosome-rich enlarged terminal axon
swellings. We also will use time-lapse microscopy to determine cell survival, with genetically-encoded pHLARE
allowing a new tool for longitudinal studies. Outcomes include resolving the functional consequences of pHlys
dynamics and dysregulated lysosome functions in ADRDs. Additionally, our parallel studies on pHlys in cancer
(parent grant) and ADRDs (supplement) have promise to identify new therapeutic approaches targeting
dysregulated pHlys to limit the progression of these diseases.
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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{{ truncateString('DIANE L BARBER', 18)}}的其他基金
Regulation of transcription factor activity in neural crest development by pH dynamics
pH 动态对神经嵴发育中转录因子活性的调节
- 批准号:
10508784 - 财政年份:2022
- 资助金额:
$ 32.02万 - 项目类别:
Regulation of transcription factor activity in neural crest development by pH dynamics
pH 动态对神经嵴发育中转录因子活性的调节
- 批准号:
10656499 - 财政年份:2022
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
9105668 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
9906489 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
9275934 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
9487198 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
10659948 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
Roles for Intracellular pH Dynamics in Cancer
细胞内 pH 动态在癌症中的作用
- 批准号:
10469119 - 财政年份:2016
- 资助金额:
$ 32.02万 - 项目类别:
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