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）生理过程中起着关键作用。 包括器官发育、组织再生和癌症转移的事件。我们的长期目标是 全面了解细胞迁移的机制，以开发新的 预防包括心血管疾病在内的疾病的发生和发展的治疗工具和策略 病理学、衰老和癌症。在PI博士后工作的基础上，该实验室探索了身体暗示如何 局部微环境（例如，约束、粘弹性、刚度、压力和剪切应力）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 最先进的微制造设备，材料，光遗传学工具，单细胞转录组学和 计算模拟以阐明压力对细胞迁移和存活力的影响。科学 本申请的前提是基于先前的研究，该研究表明细胞经历升高的压力 在迁移和侵入的各个阶段，包括外/内渗和间质迁移。虽然 人们普遍认为，细胞可以适应机械提示，但一个悬而未决的问题是， 升高的压力影响细胞在不同但生理相关的微环境中的行为。回答 这个问题，我们将研究压力和不同微环境线索之间的相互作用 （物理或生物化学）在调节细胞迁移。我们还将评估长期细胞暴露是否 高压改变了细胞运动对物理线索的敏感性。最后但并非最不重要的是，我们将剖析 在细胞死亡调节中限制和压力之间的相对作用和潜在串扰。综合起来看， 拟议的研究得到了非常令人鼓舞的初步结果的支持， 在生理环境中调节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凋亡的新治疗靶点的信息。 体内运动性。

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.