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：
8182469
负责人：
JAY T. GROVES
金额：
$ 107.14万
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/8182469
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 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 Mus Mutation Non-Malignant 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对HEW机械力的分子水平理解，可以发挥调节性控制的化学信号传导过程。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理解。为了实现这一目标，我们提出了一种高度多学科的杂交物理和生物学方法，旨在解构Hew关键的化学信号转导途径在癌症中具有重要意义的途径可以对机械输入响应于机械输入，因此，信号传导蛋白的空间组织的基本原理在不同的阶段中会导致差异化，而依赖于化学物质，而在物理上却触发了依赖的属性，而在碱性中却是一种依赖性的蛋白质，而却是一定的，并且是一种依赖的蛋白质。组织EN大分子长度尺度。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在癌症进展的定义阶段引起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）杂化细胞支撑膜连接的超分辨率成像，2）2）基于微悬臂的配体功能化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，该策略为具有化学特异性的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，并且在此也已整合。由于缺乏方法，因此，在此研究中，正在研究的化学机械信号转导耦合的类型在很大程度上被更古典的生物学方法忽略了。该项目理想地适合该中心，该中心建在物理和生物学方法的杂交中。