Fundamental Mechano-Chemical Mechanisms of Signaling in Cancer

癌症信号转导的基本机械化学机制

基本信息

批准号：
8535643
负责人：
Jan T. Liphardt
金额：
$ 39.81万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535643
关键词：
3-Dimensional Abnormal Cell Acinus organ component Behavior Biochemical Biological Biological Models Breast Breast Cancer Model Cancer Biology Cause of Death Cells Cellular biology Characteristics Chemicals Complex Coupled Drug Targeting ERBB2 gene Environment EphA2 Receptor Estrogens Genetic Goals Homeostasis Hybrid Cells Hybrids Image Investigation Laser Surgery Lateral Length Life Ligands Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Measurement Mechanics Membrane Modeling Molecular Molecular Biology Mus Mutation Non-Malignant Normal Cell Patients Phase Phenotype Process Progesterone Proteins Receptor Signaling Research Research Personnel Resolution Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Specificity Structure System Testing Therapeutic Tissues Transcend base cancer cell cancer type cantilever computerized data processing driving force erbB-2 Receptor interest mathematical model millimeter molecular scale multidisciplinary nanoscale neoplastic cell outcome forecast peer physical science programs receptor research study standard care tool triple-negative invasive breast carcinoma tumor tumor progression

项目摘要

The central hypothesis of Project I is that the spatial organization of signaling proteins is actively altered by mechanical forces and this provides a molecular scale mechanism for physical forces to directly regulate chemical signaling in cancer. The long-term goal of this proposal is tee develop a molecular level understanding of how mechanical forces can exert regulatory control over chemical signaling processes. We seek a fundamental understanding of hew the mechanical environment of a cell influences its intracellular chemical signaling. Te achieve this goal, we propose a highly multidisciplinary. hybrid physical and biological approach aimed at deconstructing how key chemical signal transduction pathways of significance in cancer can be responsive to mechanical inputs. The rationale for this is that the spatial organization of signaling proteins is altered in the different phases leading tee malignancy, and this is fundamentally net a chemical mutation in the structure of a protein, but rather a physical perturbation of protein organization on the macromolecular length scale (7, 2). The premise of our approach is that characterizing and controlling mechanical forces that drive receptor organization will allow us to elicit structural and functional phenotypes characteristic of defined phases of in cancer progression. We will target the EphA2 receptor signaling pathway as well as the Ras signaling module. These are chosen for their emerging roles in chemomechanical signal transduction. We will implement a combined approach that consists of 1) super-resolution imaging of hybrid cell-supported membrane junctions, 2) micro cantilever-based lateral force measurements of ligand-functionalized probes, and 3) nanoscissor laser surgery for cytoskeletal disruption. All three of these approaches will be employed in the context of the newly developed spatial mutation strategy, which provides unique opportunities tee mechanically perturb living cells with chemical specificity. Mathematical modeling is an essential part of all quantitative investigations and is integrated here as well.

项目I的中心假设是，信号蛋白的空间组织通过机械力积极改变，这为物理力提供了一种分子尺度机制，可以直接调节癌症中的化学信号传导。该提案的长期目标是TEE对机械力如何对化学信号传导过程产生调节性控制的分子水平了解。我们寻求对HEW细胞的机械环境的基本了解，从而影响其细胞内化学信号。 TE实现了这一目标，我们提出了一个高度的多学科。混合物理和生物学方法旨在解构癌症重要的化学信号转导途径如何对机械输入有反应。这样做的理由是，在不同阶段导致TEE恶性肿瘤中，信号蛋白的空间组织发生了变化，这在根本上是蛋白质结构中的化学突变，而是蛋白质组织在大分子长度尺度上的物理扰动（7，2）。我们方法的前提是，表征和控制驱动受体组织的机械力将使我们能够引起癌症进展中定义阶段的结构和功能表型的特征。我们将针对EPHA2受体信号通路以及RAS信号模块。这些是因为它们在化学机械信号转导中的新兴作用而选择的。我们将实施一种组合方法，该方法由1）杂化细胞支持的膜连接的超分辨率成像，2）基于微悬臂的配体功能型探针的基于微悬臂的侧向力测量以及3）纳米镜师激光手术以用于胞骨骨骼破坏。这三种方法将用于新开发的空间突变策略的背景下，该策略提供了具有化学特异性的机械扰动活细胞的独特机会。数学建模是所有定量研究的重要组成部分，并且在此也已整合。