Biophysical studies of oncogenic Cdc42Hs constructs

致癌 Cdc42Hs 构建体的生物物理研究

基本信息

项目摘要

DESCRIPTION (provided by applicant): Cdc42Hs, a member of the Ras superfamily signal transduction proteins, binds guanine nucleotides and acts as a molecular timing switch in multiple signal transduction pathways. This proposal is centered around studying the structure and dynamics of Cdc42Hs forms associated with its oncogenic potential and will provide atomic level information into mechanisms that regulate this activity. The Cdc42Hs constructs that will be studied are, A) Cdc42Hs(nucleotide-free) and, B) Cdc42Hs(F28L_?L8). Defining the structure and dynamics of the nucleotide-depleted form of Cdc42Hs will shed light on the conformation(s) of Cdc42Hs that facilitate the binding of protein effectors, such as Dbl, that stimulate oncogenic activity. The study of the structure and dynamics of Cdc42Hs(F28L_?L8) should reveal information on interactions in Cdc42Hs that block oncogenic activity caused by the single mutant Cdc42Hs(F28L). The immediate goals of this research are to use NMR and fluorescence as structural techniques to gain a better understanding of the processes by which changes in Cdc42Hs and its interaction with regulators affect various important signal transduction pathways that lead to cancer. The long-term goals of this proposed research are to gain a better understanding of how protein structure and dynamics correlate with aberrant cell function, which will lay the foundation for future research into the development of a rational anti-cancer drug design program. Cdc42Hs is a member of the Ras superfamily of proteins, which have been implicated in cancers in the colon, breasts, and lungs. These studies will provide information on particular aspects of specific cell-signaling processes that may be subsequently used in the development of new anti-cancer treatments that are specific and may be less toxic than traditional chemotherapy approaches. I have a background in the use of fluorescence spectroscopy in the study of biological molecules and have used NMR spectroscopy to study structure of small peptides in solution. The mentored phase of this proposal will provide me with the opportunity to gain experience in several uses of these techniques that have not yet been mastered that will be crucial to my transition to independent investigation. The Department of Molecular Medicine at Cornell University has great experience in the area of applying physical methods to biological processes, and in particular, signal transduction. It is an excellent setting for this project, and also to foster the development of my career. The research career development plan of this proposal is two-phased. Phase I (Mentored) will allow for the study of the nucleotide-free construct of Cdc42Hs. The experience with the structural tools, data analysis procedures, and scientific collaboration in this phase will foster the necessary preparation for a successful transition into Phase II (Independent), during which time I will study the structure and dynamics of Cdc42Hs(F28L_?L8), leading to further research in the structural biology of biomolecules related to cancer.
描述(由申请人提供):Cdc42H是Ras超家族信号转导蛋白的成员,结合鸟嘌呤核苷酸,并在多个信号转导途径中充当分子定时开关。该提案围绕研究与其致癌潜力相关的Cdc42Hs形式的结构和动力学,并将为调节这种活动的机制提供原子水平的信息。将被研究的Cdc42 Hs构建体是,A)Cdc42 Hs(无核苷酸)和,B)Cdc42 Hs(F28 L_?L8)。确定Cdc42H的核苷酸缺失形式的结构和动力学将揭示Cdc42H的构象,其促进刺激致癌活性的蛋白质效应物(如Dbl)的结合。研究了Cdc42Hs(F28L_?L8)应该揭示Cdc42H中的相互作用的信息,所述相互作用阻断由单个突变体Cdc42H(F28L)引起的致癌活性。 本研究的直接目标是使用NMR和荧光作为结构技术,以更好地了解Cdc42Hs的变化及其与监管机构的相互作用影响导致癌症的各种重要信号转导途径的过程。这项研究的长期目标是更好地了解蛋白质结构和动力学如何与异常细胞功能相关,这将为未来研究开发合理的抗癌药物设计方案奠定基础。Cdc42Hs是Ras蛋白超家族的成员,与结肠癌、乳腺癌和肺癌有关。这些研究将提供有关特定细胞信号传导过程的特定方面的信息,这些信息随后可能用于开发新的抗癌治疗方法,这些治疗方法具有特异性,并且可能比传统的化疗方法毒性更小。我有荧光光谱学在生物分子研究中的应用背景,并使用NMR光谱学研究溶液中小肽的结构。本建议的辅导阶段将使我有机会在使用这些尚未掌握的技术方面获得经验,这对我过渡到独立调查至关重要。康奈尔大学分子医学系在将物理方法应用于生物过程,特别是信号转导方面具有丰富的经验。这是一个很好的设置为这个项目,也促进了我的职业生涯的发展。本提案的研究职业发展计划分为两个阶段。第一阶段(指导)将允许研究Cdc42Hs的无核苷酸构建体。在这一阶段的结构工具,数据分析程序和科学合作的经验将促进必要的准备,成功过渡到第二阶段(独立),在此期间,我将研究Cdc42Hs(F28L_?L8),导致进一步研究与癌症相关的生物分子的结构生物学。

项目成果

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PAUL Damien ADAMS其他文献

PAUL Damien ADAMS的其他文献

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{{ truncateString('PAUL Damien ADAMS', 18)}}的其他基金

Monovalent Nanocrystals for Biomedical Imaging
用于生物医学成像的单价纳米晶体
  • 批准号:
    7904025
  • 财政年份:
    2009
  • 资助金额:
    $ 10.8万
  • 项目类别:
Monovalent Nanocrystals for Biomedical Imaging
用于生物医学成像的单价纳米晶体
  • 批准号:
    7707451
  • 财政年份:
    2009
  • 资助金额:
    $ 10.8万
  • 项目类别:
Biophysical studies of oncogenic Cdc42Hs constructs
致癌 Cdc42Hs 构建体的生物物理研究
  • 批准号:
    7667244
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Biophysical studies of oncogenic Cdc42Hs constructs
致癌 Cdc42Hs 构建体的生物物理研究
  • 批准号:
    8103146
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Biophysical studies of oncogenic Cdc42Hs constructs
致癌 Cdc42Hs 构建体的生物物理学研究
  • 批准号:
    7912935
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Biophysical studies of oncogenic Cdc42Hs constructs
致癌 Cdc42Hs 构建体的生物物理研究
  • 批准号:
    7494160
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
Biophysical studies of oncogenic Cdc42Hs constructs
致癌 Cdc42Hs 构建体的生物物理研究
  • 批准号:
    7201874
  • 财政年份:
    2007
  • 资助金额:
    $ 10.8万
  • 项目类别:
PROJECT 1 - LAWRENCE BERKELEY LAB - PHENIX
项目 1 - 劳伦斯伯克利实验室 - 凤凰城
  • 批准号:
    7208309
  • 财政年份:
    2006
  • 资助金额:
    $ 10.8万
  • 项目类别:
PROJECT 1 - LAWRENCE BERKELEY LAB - PHENIX
项目 1 - 劳伦斯伯克利实验室 - 凤凰城
  • 批准号:
    7673541
  • 财政年份:
  • 资助金额:
    $ 10.8万
  • 项目类别:
PROJECT 1 - LAWRENCE BERKELEY LAB - PHENIX
项目 1 - 劳伦斯伯克利实验室 - 凤凰城
  • 批准号:
    7908729
  • 财政年份:
  • 资助金额:
    $ 10.8万
  • 项目类别:

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