Connecting Ca2+ and cell migration to development and cancer

细胞内钙离子浓度的变化推动了许多细胞事件的发生，从生命的一开始(受精)，到发育，最后到细胞死亡。这些Ca~(2+)信号通常起源于细胞内的Ca~(2+)库，它包括各种酸性细胞器，如被称为“酸性Ca~(2+)库”的溶酶体。通过酸性钙离子储存的信号缺陷与包括帕金森病在内的许多疾病有关，这突显了了解细胞器钙离子运输及其调节的细胞过程的必要性。神经脊是在所有脊椎动物胚胎中发现的一种短暂的、迁移的细胞群体，可分化为广泛的细胞类型，包括周围神经系统的神经元和神经胶质细胞，以及头部的软骨和骨骼元素。了解推动迁移的机制对于了解形态发生和癌症转移至关重要--这是一个通常与神经脊迁移相似的过程。这个项目建立在我们最近的发现基础上，这些发现发现了酸性钙离子储存上的新的钙转运体，并表明它们调节体内神经脊细胞的迁移。总体目标是结合溶酶体内钙信号传递(Patel)和细胞迁移(Mayor)方面的专业知识，进一步验证细胞运动需要酸性钙存储的假设。学生将使用化学和分子方法来操纵钙离子信号蛋白，并研究其对细胞内钙离子和迁移的影响。这将通过一系列分子细胞生物学和成像方法，两栖类神经脊细胞在体内研究细胞迁移，以及神经母细胞瘤，最常见的儿童癌症之一，用于体外分析。该项目的成功结果将为在(病理)生理相关过程中内溶酶体内钙信号和细胞迁移的机制提供迫切需要的分子洞察。

Changes in the concentration of cytosolic Ca2+ drive a multitude of cellular events from those at the very start of life (fertilization), through development and ultimately to those culminating in cell death. These Ca2+ signals often initiate from intracellular Ca2+ stores which includes a variety of acidic organelles such as lysosomes referred to as "acidic Ca2+ stores". Defective signalling through acidic Ca2+ stores has been implicated in a number of disorders including Parkinson disease highlighting the need to understand organellar Ca2+ transport and the cellular processes that it regulates.The neural crest is a transient, migratory population of cells found in all vertebrate embryos that differentiate into a wide range of cell types, including neurons and glial cells of the peripheral nervous system and cartilaginous and skeletal elements in the head. Understanding the mechanisms driving migration is critically important to understand not only morphogenesis but also cancer metastasis - a process to which neural crest migration is often likened.This project builds on our very recent findings that have identified novel Ca2+ transporters on acidic Ca2+ stores and shown that they regulate migration of neural crest cells in vivo. The overall aim is to combine expertise in endo-lysosomal Ca2+ signalling (Patel) and cell migration (Mayor) to further test the hypothesis that acidic Ca2+ stores are required for cell motility. The student will use both chemical and molecular methods to manipulate Ca2+ signaling proteins and examine the effect on cytosolic Ca2+ and migration. This will be achieved using a range of molecular cell biology and imaging approaches, amphibian neural crest cells to study cell migration in vivo, and neuroblastoma, one of the most common childhood cancers, for in vitro analyses.The successful outcome of this project will provide urgently needed molecular insight in to the mechanisms of endo-lysosomal Ca2+ signalling and cell migration during (patho)physiologically relevant processes.