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：
8324738
负责人：
JAY T. GROVES
金额：
$ 103.88万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8324738
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 Delivery Systems 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 Methodology 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 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 long-term goal of this proposal is to develop a molecular level understanding of hew mechanical forces can exert regulatory control ever chemical signaling processes. We seek a fundamental understanding of how the mechanical environment of a cell influences its intracellular chemical signaling. To achieve this goal we propose a highly multidisciplinary, hybrid physical and biological approach aimed at deconstructing hew 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 to malignancy, and this is fundamentally net a chemical mutation in the structure of a protein, but rather a physical perturbation to protein organization en the macromolecular length scale. 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 in defined phases of 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 to mechanically perturb living cells with chemical specificity. Mathematical modeling is an essential part of all quantitative investigations and is integrated here as well. The types of chemomechanical signal transduction couplings under investigation here have been largely overlooked by more classical biological approaches because of lack of methodology. This project is ideally suited to this center, which is built in the hybridization of physical and biological approaches.

该提案的长期目标是在分子水平上理解机械力可以对化学信号传导过程进行调节控制。我们寻求对细胞的机械环境如何影响其细胞内化学信号传导的基本了解。为了实现这一目标，我们提出了一种高度多学科、混合物理和生物学的方法，旨在解构癌症中重要的关键化学信号转导途径可以对机械输入做出反应。这样做的基本原理是，信号蛋白的空间组织在不同的阶段导致恶性肿瘤，这从根本上来说是蛋白质结构的化学突变，而是大分子长度尺度上蛋白质组织的物理扰动。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出癌症进展的特定阶段的结构和功能表型特征。我们将针对 EphA2 受体信号传导通路以及 Ras 信号传导模块。选择它们是因为它们在化学机械信号转导中的新兴作用。我们将实施一种组合方法，包括：1）混合细胞支持的膜连接的超分辨率成像，2）基于微悬臂梁的配体功能化探针的侧向力测量，以及3）用于细胞骨架破坏的纳米剪刀激光手术。所有这三种方法都将在新开发的空间突变策略的背景下使用，该策略为以化学特异性机械扰动活细胞提供了独特的机会。数学建模是所有定量研究的重要组成部分，也集成在这里。由于缺乏方法论，这里所研究的化学机械信号转导耦合的类型在很大程度上被更经典的生物学方法所忽视。该项目非常适合该中心，该中心是采用物理和生物方法相结合而建立的。