Dynamic decisions: Integrating dynamic gene expression with mechanical signals to understand retinogenesis and ocular disorders.

器官的生长是一个复杂的过程，需要严格控制，以确保身体结构的正确组织。细胞群必须协调运动和改变形状，以决定增殖或专门化成成熟器官的成熟细胞类型。我最近的研究表明，在器官生长过程中，基因并不是简单的开或关。相反，一些基因的水平会随着时间的推移而动态变化，这有助于控制细胞是否决定增殖或特化。目前尚不清楚细胞形状、组织折叠和力学的变化如何与细胞决策过程中基因活动的脉冲协调。这在胚胎眼睛发育和生长中特别重要。某些感知力和组织力学的蛋白质的遗传变化会导致眼部疾病，如缺损和小眼球。当子宫中眼睛生长的发育步骤顺序被打乱时，这些眼睛疾病就会发生。患有小眼症的儿童有发育不全的小眼睛。那些有缺损的人在眼睛的一个或多个结构中有裂缝或洞，如视网膜。这些情况会影响视力，目前没有治疗方法。缺损（一种结构性组织疾病）和小眼球（一种细胞决策障碍）同时发生，表明组织力学和细胞决策之间存在双向联系。我将研究在发育中的眼睛中，组织折叠和运动的力量如何随着时间的推移影响细胞命运基因的活性。我将使用最先进的实时成像技术，显示基因活动在真实的时间。我将把在缺损和小眼球患者中看到的遗传变化引入培养皿中生长的“迷你眼睛”中，以研究这些疾病是如何发生的。了解机械信号和细胞决策之间的联系将有助于开发创新的基于细胞的疗法。因此，我的工作对进一步了解发育性眼部疾病和创新的再生医学方法具有重要意义。

The growth of an organ is a complex process that needs to be tightly controlled to ensure that structures in the body are correctly organised. Groups of cells must co-ordinate moving and changing shape with decisions to proliferate or specialise into mature cell types of the adult organ. My recent work has shown that during organ growth, genes are not simply on or off. Instead, the levels of some genes pulse dynamically over time, and this helps control whether cells decide to proliferate or specialise. It is not clear how changes in cell shape, tissue folding and mechanics are co-ordinated with the pulses in gene activity during cell decisions. This is particularly important in embryonic eye development and growth. Genetic changes in certain proteins which sense forces and tissue mechanics can lead to the eye disorders coloboma and microphthalmia. These eye disorders occur when the sequence of developmental steps in the growth of an eye in the womb are disrupted. Children born with microphthalmia have small under-developed eyes. Those with coloboma have a cleft or hole in one or more structures of the eye, such as the retina. These conditions affect vision, and there are currently no treatments. That coloboma, a structural tissue disorder, and microphthalmia, a disorder of cellular decisions, occur together suggests a two-way link between tissue mechanics and cell decisions. I will investigate how, within the developing eye, forces from tissue folding and movement affect cell fate gene activity over time. I will use state-of-the-art live imaging techniques that show gene activity in real time. I will introduce the genetic changes seen in coloboma and microphthalmia patients into 'mini-eyes' grown in a dish to investigate how these disorders occur. Understanding the links between mechanical signals and cell decisions will support development of innovative cell-based therapies. My work therefore has important implications for furthering understanding of developmental ocular disorders and innovative regenerative medicine approaches.