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

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)
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DIANE L BARBER其他文献

DIANE L BARBER的其他文献

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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:
Regulation of Epithelial Plasticity
上皮可塑性的调节
  • 批准号:
    9103387
  • 财政年份:
    2015
  • 资助金额:
    $ 32.02万
  • 项目类别:
Regulation of Epithelial Plasticity
上皮可塑性的调节
  • 批准号:
    8888935
  • 财政年份:
    2015
  • 资助金额:
    $ 32.02万
  • 项目类别:

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