Bioelectrical signals in controlling the morphogenesis of the embryonic stem cells

了解控制细胞增殖和运动的机制是预防、检测和治疗癌症的重要组成部分。目前的研究主要集中在生化信号因子和基因转录网络上。作为这种方法的补充，本研究提出在分子水平上理解细胞行为的表观遗传生物物理控制。利用多学科方法（分子遗传学和体内生理学），本项目将研究离子流作为细胞类型、位置和分化的内源性调节剂的作用。通过发现和表征离子转运体的新作用，H+和K+流动（以及pH和膜电压梯度）已经与左右模式、脊髓/肌肉再生和眼睛发育有关。肿瘤细胞在细胞内pH值和膜电位上与正常细胞不同。大量数据表明，这些生物电参数不仅仅是其他事件的简单副产品，而是具有指导意义的功能信号，通过这些信号可以控制细胞的行为。其中一个最显著的例子是细胞在生理电场作用下的明显极性和定向运动，这对发育和组织重塑至关重要。该研究建议利用操纵和表征生物电事件的专业知识，以及高度易于处理的模型系统，并适用于最先进的分子遗传学和生理学技术，以在这一新颖但非常重要的癌症生物学方面取得进展。

Understanding mechanisms that control proliferation and movement of cells is an essential component of efforts to prevent, detect, and treat cancer. Most current efforts focus on biochemical signaling factors and gene transcription networks. Complementary to this approach, this research proposes to understand, at the molecular level, epigenetic biophysical controls of cell behavior. Using multi-disciplinary approaches (molecular genetics and in vivo physiology) this proposed project will address the roles of ion flows as an endogenous regulator of cell type, position, and differentiation. By discovering and characterizing novel roles of ion transporters, H+ and K+ flows (and pH and membrane voltage gradients) have been already implicated in left-right patterning, spinal cord/muscle regeneration, and eye development. Tumor cells often differ from normal cells in their intracellular pH and membrane voltage potential. Numerous data indicate that these bioelectrical parameters are not simply house-keeping byproducts of other events but are rather instructive, functional signals by means of which cell behavior can be controlled. One of the most striking examples for this is distinct polarity and directional movement of cells, both crucial for development and tissue remodeling, under physiological electric fields. The research proposes to capitalize on the expertise in manipulating and characterizing bioelectrical events, as well as on a model system that is highly tractable and amenable to state-of-the-art techniques of molecular genetics and physiology, to make progress in this novel but very important aspect of cancer biology.