Cell mechanoresponses in physiologically relevant microenvironments

摘要：细胞迁移是一种基本的细胞现象，在（病理）生理学中发挥着关键作用。 事件，包括器官发育、组织再生和癌症转移。我们的长期目标是 全面了解细胞迁移机制，以开发新的 预防疾病（包括心血管疾病）发生和进展的治疗工具和策略 病理、衰老和癌症。在 PI 博士后工作的基础上，实验室探索了物理线索如何 局部微环境（例如，约束、粘弹性、刚度、压力和剪切应力）的转换 转化为生化信号来影响细胞的迁移行为。未来五年，我们将聘用 最先进的微加工设备、材料、光遗传学工具、单细胞转录组学和 计算模拟来阐明压力对细胞迁移和活力的影响。科学的 该应用的前提基于先前的研究，表明细胞经历升高的压力 在迁移和入侵的各个阶段，包括外/内渗和间质迁移。虽然 人们普遍认为细胞可以适应机械信号，但一个开放且未解决的问题是如何适应 升高的压力会影响多种但具有生理相关性的微环境中的细胞行为。来回答 对于这个问题，我们将研究压力与不同微环境线索之间的相互作用 （物理或生化）细胞迁移的调节。我们还将评估长期的细胞暴露是否 高压会改变细胞运动对物理信号的敏感性。最后但并非最不重要的一点是，我们将剖析 限制和压力在细胞死亡调节中的相对作用和潜在的串扰。综合起来， 拟议的研究得到了非常令人鼓舞的初步结果的支持，将描绘出 调节生理环境中细胞行为的潜在机制并产生新的概念 有助于识别旨在促进或预防细胞增殖的新治疗靶点的信息 体内的运动能力。

Summary: Cell migration is a fundamental cellular phenomenon that plays a pivotal role in (patho)physiological events, including organ development, tissue regeneration and cancer metastasis. Our long-term goal is to achieve a comprehensive understanding of the mechanisms of cell migration in order to develop novel therapeutic tools and strategies to prevent the initiation and progression of diseases, including cardiovascular pathologies, aging, and cancer. Building on the PI's postdoctoral work, the lab explores how the physical cues of the local microenvironment (e.g., confinement, viscoelasticity, stiffness, pressure and shear stress) convert into biochemical signals to influence the migratory behavior of cells. Over the next five years, we will employ state-of-the-art microfabricated devices, materials, optogenetic tools, single-cell transcriptomics and computational simulations to elucidate the effects of pressure forces on cell migration and viability. The scientific premise of this application is based on prior studies showing that cells experience elevated pressure forces during various stages of migration and invasion, including extra/intravasation and interstitial migration. Although the widely held view is that cells can adapt to mechanical cues, an open and unaddressed question is how elevated pressure affects cell behavior in diverse, yet physiologically relevant, microenvironments. To answer this question, we will investigate the interplay between pressure forces and different microenvironmental cues (physical or biochemical) in the regulation of cell migration. We will also assess whether long-term cell exposure to high pressures alters the sensitivity of cell motility to physical cues. Last but not least, we will dissect the relative roles and potential crosstalk between confinement and pressure in cell death regulation. Taken together, the proposed studies, which are supported by highly encouraging preliminary results, will delineate the underlying mechanisms regulating cell behavior in physiological environments and generate novel conceptual information that will facilitate the identification of new therapeutic targets aimed at promoting or preventing cell motility in vivo.