Cortical excitability as a mechanism for epithelial barrier maintenance: A joint experiment-theory systems approach

多细胞生物进化出多种适应，以分离和保护自己免受周围环境的影响，这些环境通常对生物体内部有害。上皮组织在我们的身体中扮演着守护的角色，包裹着整个身体（皮肤）以及我们的每个器官。这种保护作用依赖于单个上皮细胞之间紧密连接的形成和持续维持。这些连接必须足够紧密，以阻止病原体、外来蛋白质、化学物质和气体的进入，并保持在体液内。多种使人衰弱的人类疾病与肠道、肺、皮肤、粘膜等这些保护屏障的丧失有关。然而，上皮组织是活的，上皮内的单个细胞经历细胞分裂、死亡和重排，所有这些过程都要求细胞之间的连接必须是塑性的和动态的。在活的和活跃发育的上皮细胞中屏障功能是如何维持的仍然知之甚少。研究青蛙胚胎上皮，我们最近发现，由于机械张力增加，这种动态组织中的细胞-细胞连接经历随机失效（破裂），但通过某种方式由破裂触发的哨兵机制迅速修复。我们的数据表明，这种修复过程的分子机制可能涉及一种被称为兴奋性的基本系统特性，这种特性在所有科学和技术领域的复杂非线性系统中都可以观察到。我们最近在青蛙和海星的卵母细胞中描述了一种可能类似的兴奋行为，这一发现发表在2015年11月的《自然细胞生物学》杂志上，并在BBSRC新闻和商业杂志上发表。在本提案中，我们将利用现代实验方法和计算模型在深度和广度上探索上皮修复机制的可兴奋性假设。我们将确定这一机制的分子细节，并将在这一机制中寻求干预点，以便最终将我们的结果转化为新的医学疗法。

Multicellular organisms evolved multiple adaptations to separate and protect themselves from the surrounding environment, which is frequently hostile to the interior of the organism. Epithelial tissues in our bodies play the guardian role enveloping the entire body (skin) as well as wrapping each of our organs. This protective role relies on the formation and continuous maintenance of tight junctions between individual epithelial cells. These junctions have to be sufficiently tight to prohibit entry of pathogens, foreign proteins, chemicals and gases as well as to keep inside the bodily fluids. Multiple debilitating human diseases are associated with loss of these protection barriers in the gut, lungs, skin, mucosa, etc. However, epithelial tissues are live and individual cells within epithelium undergo cell divisions, death and rearrangements, all process that require that the junctions between cells must be plastic and dynamic. How the barrier function is maintained within living and actively developing epithelia remains still poorly understood. Studying frog embryonic epithelium, we recently discovered that cell-cell junctions in this dynamic tissue undergo random failures (ruptures) due to the increased mechanical tension but are rapidly repaired by a sentinel mechanism that is somehow triggered by the rupture. Our data suggest that the molecular mechanism of this repair process may involve a fundamental systemic property known as excitability, which is observed in complex nonlinear systems across all areas of science and technology. We recently described a likely similar excitable behavior in frog and starfish oocytes and this discovery, published in November 2015 by Nature Cell Biology, was featured in the BBSRC News and Business Magazine. In this proposal we will explore the hypothesis of the excitable nature of the epithelium repair mechanism in depth and breadth using both modern experimental methods and computational modelling. We will identify the molecular details of this mechanism and will seek points of intervention within this mechanism to be able to eventually translate our results into novel medical therapies.