Elucidating the Role of Akt and Keratins in Autophagy and Tumorigenesis

阐明 Akt 和角蛋白在自噬和肿瘤发生中的作用

基本信息

  • 批准号:
    8903736
  • 负责人:
  • 金额:
    $ 14.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-10 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The NIH K08 mentored career development award provides the necessary foundation for me to fulfill my long-term career goals of being an independently-funded translational investigator focusing on the therapeutic manipulation of autophagy in the treatment of cancer. The mentored award will also help me achieve my immediate goals of obtaining expertise both in autophagy research and in the management of non- melanoma skin cancer. Under the auspices of the University of Texas Southwestern Medical Center at Dallas, I hope to attain these objectives through the following: 1) career mentorship from internationally recognized physicians and scientists who are experts in autophagy, dermatology, and cancer biology, 2) specific guidance in the form of structured reading and courses, which I will apply to experiments and patient care. My mentored research project centers on a novel model for the regulation of autophagy by Akt and keratin intermediate filaments and tests this model for its effects on tumorigenesis; our model challenges the current paradigm that the regulation of autophagy occurs primarily through mTOR. Addressing the question of how autophagy is regulated will be essential not only for interpreting the results of ongoing clinical trials but also for improving the way autophagy is manipulated in future cancer therapies. Aim 1 tests our hypothesis that Akt and phosphorylation of Beclin 1 directly regulate autophagy. First, we will test our hypothesis that Akt can regulate autophagy independently of mTOR through phosphorylation of Beclin 1. Next, we will determine how the status of PI3K-Akt activation in cancer cells affects the phosphorylation of Beclin 1. Finally, we will address what effects the phosphorylation of Beclin 1 has on autophagy and cell proliferation in cancer cell lines. Aim 2 will test whether the phosphorylation of epithelial keratins regulates autophagy in vitro and whether known pathogenic keratin mutations affect autophagy and cell proliferation. First, mutant intermediate filament (IF) proteins and cells deficient for specific IFs cells will b tested for their effects on autophagy in established in vitro assays. Next, we will determine whether this inhibition of autophagy results in excess cell proliferation in vitro. Finally, we wil use mouse models with keratin defects (both deletions and mutations) to test whether impaired autophagy contributes to keratinopathies and tumorigenesis. Aim 3 will test what effects the disruption of the predicted complex has on tumorigenesis in in vitro assays and in vivo mouse models. The effects of IF mutations on tumorigenesis will be determined in vitro. Next, we will test whether the chemical induction of autophagy or genetic induction of autophagy through disruption of proposed regulatory complex can prevent tumorigenesis in vivo. These studies will employ an established model of non-melanoma skin cancer formation in skin with an inducible deletion of PTEN. These studies will transform our current understanding of how autophagy is regulated and impact how autophagy is manipulated to treat cancer in future clinical trials.
描述(申请人提供):NIH K08导师职业发展奖为我实现长期职业目标提供了必要的基础,我的长期职业目标是成为一名独立资助的翻译研究员,专注于癌症治疗中自噬的治疗性操作。导师奖还将帮助我实现在自噬研究和非黑色素瘤皮肤癌管理方面获得专业知识的直接目标。在达拉斯德克萨斯大学西南医学中心的赞助下,我希望通过以下方式实现这些目标:1)来自国际知名医生和科学家的职业指导,他们是自噬、皮肤病和癌症生物学方面的专家;2)以结构化阅读和课程的形式提供具体指导,我将把这些指导应用于实验和患者护理。我的指导研究项目集中在一个新的模型上,该模型用于调节Akt和角蛋白中间丝的自噬,并测试该模型对肿瘤发生的影响;我们的模型挑战了目前的范式,即自噬的调节主要通过mTOR发生。解决如何调控自噬的问题不仅对于解释正在进行的临床试验的结果,而且对于改进未来癌症治疗中操纵自噬的方式也是至关重要的。目的1验证Akt和Beclin 1的磷酸化直接调节自噬的假设。首先,我们将验证我们的假设,即Akt可以通过Beclin 1的磷酸化独立于mTOR来调节自噬。接下来,我们将确定癌细胞中PI3K-Akt的激活状态如何影响Beclin 1的磷酸化。最后,我们将讨论Beclin 1的磷酸化对癌细胞株的自噬和细胞增殖的影响。目的2将测试上皮角蛋白的磷酸化是否在体外调节自噬,以及已知的致病角蛋白突变是否影响自噬和细胞增殖。首先,在建立的体外检测中,将测试突变的中间丝(IF)蛋白和缺乏特定IF细胞的细胞对自噬的影响。接下来,我们将确定这种对自噬的抑制是否会导致体外细胞过度增殖。最后,我们将使用角蛋白缺陷(缺失和突变)的小鼠模型来测试自噬受损是否有助于角质病和肿瘤的发生。目的3将在体外试验和体内小鼠模型中测试预测的复合体的破坏对肿瘤发生的影响。IF突变对肿瘤发生的影响将在体外确定。接下来,我们将测试通过破坏拟议的调控复合体来化学诱导自噬或通过基因诱导自噬是否可以防止体内肿瘤的发生。这些研究将采用已建立的皮肤非黑色素瘤皮肤癌形成模型,其中PTEN基因可诱导缺失。这些研究将改变我们目前对自噬如何被调控的理解,并在未来的临床试验中影响如何操纵自噬来治疗癌症。

项目成果

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Richard C Wang其他文献

Richard C Wang的其他文献

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{{ truncateString('Richard C Wang', 18)}}的其他基金

Regulation and Function of Viral and Endogenous Circular RNA in Cancer
病毒和内源性环状RNA在癌症中的调节和功能
  • 批准号:
    10753361
  • 财政年份:
    2023
  • 资助金额:
    $ 14.33万
  • 项目类别:
Regulation and Function of Human Polyomavirus circular RNAs
人多瘤病毒环状RNA的调控和功能
  • 批准号:
    10598409
  • 财政年份:
    2022
  • 资助金额:
    $ 14.33万
  • 项目类别:
Mechanisms of Glucose Dependence in Proliferating Cells
增殖细胞的葡萄糖依赖性机制
  • 批准号:
    9895626
  • 财政年份:
    2018
  • 资助金额:
    $ 14.33万
  • 项目类别:
Mechanisms of Glucose Dependence in Proliferating Cells
增殖细胞的葡萄糖依赖性机制
  • 批准号:
    10380590
  • 财政年份:
    2018
  • 资助金额:
    $ 14.33万
  • 项目类别:
Dermatology Research Training Program
皮肤科研究培训计划
  • 批准号:
    10618235
  • 财政年份:
    2014
  • 资助金额:
    $ 14.33万
  • 项目类别:
Elucidating the Role of Akt and Keratins in Autophagy and Tumorigenesis
阐明 Akt 和角蛋白在自噬和肿瘤发生中的作用
  • 批准号:
    8713422
  • 财政年份:
    2012
  • 资助金额:
    $ 14.33万
  • 项目类别:
Elucidating the Role of Akt and Keratins in Autophagy and Tumorigenesis
阐明 Akt 和角蛋白在自噬和肿瘤发生中的作用
  • 批准号:
    8541786
  • 财政年份:
    2012
  • 资助金额:
    $ 14.33万
  • 项目类别:
Elucidating the Role of Akt and Keratins in Autophagy and Tumorigenesis
阐明 Akt 和角蛋白在自噬和肿瘤发生中的作用
  • 批准号:
    8383935
  • 财政年份:
    2012
  • 资助金额:
    $ 14.33万
  • 项目类别:

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