Kinase Control of Synergistic Cell Migration Mechanics

协同细胞迁移机制的激酶控制

基本信息

批准号：
10618280
负责人：
Michelle Christine Mendoza
金额：
$ 30.78万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-10 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618280
关键词：
Actins Acute Adhesions Basic Science Binding Biology Biosensor Bundling Carcinoma Cell Adhesion Cell membrane Cell model Cell physiology Cells Collagen Computer Models Coupled Data Development Disease Epithelial Cells Foundations Gel Goals Image Individual Integrins Invaded Knowledge Lighting Location MAP3K1 gene MEKs Malignant Neoplasms Measurement Measures Mechanics Mediating Membrane Migration Assay Modeling Molecular Motion Mutation Neoplasm Metastasis Oncogenes Output Pathologic Pattern Phosphorylation Phosphorylation Site Phosphotransferases Physiological Polymers Process Protein Kinase Proteins Public Health Receptor Activation Receptor Protein-Tyrosine Kinases Regulation Relaxation Research Role Signal Pathway Signal Transduction Site Testing Traction Width Work ZYX gene cancer cell cell motility ezrin improved innovation migration mutant novel therapeutic intervention optogenetics permissiveness polymerization prevent recruit scaffold spatiotemporal therapeutic target time use tool treatment strategy wound healing

项目摘要

Project Abstract Cell migration is a fundamental cellular process necessary for development and coopted in diseases like cancer metastasis. Our long-term goal is to elucidate the signals that control migration and cancer invasion, so that treatment strategies to reduce pathological migration and cancer metastasis can be improved. Fluctuations in cell migration forces control leading edge protrusion-retraction cycles, but we do not know what controls the force fluctuations. The overall objective here is to understand the signaling mechanisms that control and integrate the fluctuating molecular forces of cell migration. Signaling pathways can act by directing spatially-localized and coordinated fluctuations in actin, adhesion, and membrane tension paramters (instructive). Alternatively, signaling pathways may instruct some processes and act without spatiotemporal precision (permissive) in others. We will elucidate the cell migration control mechanisms by dissecting the temporal and spatial regulation of the protein kinase ERK and its signaling outputs in untransformed and cancer cells. ERK acts on multiple steps in the protrusion-retraction cycle. The disease-relevant cancer cells model a high-activity state, in which ERK activity is upregulated due to onocogenic mutations. Our central hypothesis is that ERK instructs spatially- localized synergistic fluctuations in actin assembly, adhesion lifetime, and membrane tension for edge motion and cell migration. For the first aim, we will measure the temporal fluctuations in ERK activity during edge protrusion and retraction using modified ERK biosensors. We will incorporate the experimentally-observed activity fluctuations into a computational model and experimental tests to determine which patterns dictate protrusion velocity and persistence. For the second aim, we will determine if spatiatially-organized ERK activity controls edge motion. We will test membrane and adhesion-activated ERK for the ability to induce protrusion experimentally and computationally. We will also test how the pattern of ERK retention in the membrane and adhesion domains contributes to protrusion power and width. For the third aim, we will test if ERK is controls membrane tension and adhesion lifetime for protrusion velocity. We will test signaling through Zyxin and Ezrin to actin as possible mechanisms by which ERK controls these additional for molecular forces. The proposed research is conceptually innovative because it tests the role of fluctuating ERK signals in the regulation of cell migration. It is technically innovative in the development and use of new optogenetics tools and computational models. The research is significant because it has the potential to reveal a new principle about how molecular forces are integrated to bring about motion. It will also identify scaffolds and signals that control local ERK activity fluctuations that could be adapted for new therapeutic strategies to control cell adhesion and migration.

项目摘要细胞迁移是发育所必需的基本细胞过程，并与疾病相关癌症转移。我们的长期目标是阐明控制迁移和癌症侵袭的信号，因此可以改进减少病理迁移和癌症转移的治疗策略。波动在细胞迁移中，力控制前缘突出-缩回循环，但我们不知道是什么控制着力的波动。这里的总体目标是了解控制和集成的信号机制细胞迁移的波动分子力。信号通路可以通过引导空间局部化和肌动蛋白、粘附和膜张力参数的协调波动（指导性）。或者，信号通路可能指导某些过程，并在其他过程中没有时空精确性（允许）地发挥作用。我们将通过剖析细胞迁移的时间和空间调控来阐明细胞迁移控制机制。蛋白激酶 ERK 及其在未转化细胞和癌细胞中的信号输出。 ERK 作用于多个步骤突出-缩回循环。与疾病相关的癌细胞模拟高活性状态，其中 ERK 由于致癌突变，活性上调。我们的中心假设是 ERK 指示空间- 肌动蛋白组装、粘附寿命和边缘运动的膜张力的局部协同波动和细胞迁移。对于第一个目标，我们将测量边缘期间 ERK 活动的时间波动使用改良的 ERK 生物传感器进行突出和缩回。我们将结合实验观察到的将活动波动纳入计算模型和实验测试以确定哪些模式决定突出速度和持久性。对于第二个目标，我们将确定空间组织的 ERK 活动是否控制边缘运动。我们将测试膜和粘附激活的 ERK 诱导突出的能力通过实验和计算。我们还将测试 ERK 在膜中的保留模式和粘附域有助于突出功率和宽度。对于第三个目标，我们将测试 ERK 是否为对照突出速度的膜张力和粘附寿命。我们将通过 Zyxin 和 Ezrin 测试信号传递作为 ERK 控制这些额外分子力的可能机制。拟议的该研究在概念上具有创新性，因为它测试了波动的 ERK 信号在细胞调节中的作用迁移。它在新光遗传学工具和计算的开发和使用方面具有技术创新模型。这项研究意义重大，因为它有可能揭示分子如何运作的新原理力量被整合以产生运动。它还将识别控制局部 ERK 活性的支架和信号波动可以适应新的治疗策略来控制细胞粘附和迁移。