MRC Transition Support CDA Yanlan Mao

随着我们的发育，我们的组织和器官如何知道当它们达到正确的大小和形状时何时停止生长？它们如何在整个成年期保持正确的大小和形状呢？如果他们受伤了，他们如何恢复自己的大小和形状？这些过程的错误调节可导致过度生长的疾病，如癌症和瘢痕。我们能否从一个新的角度来理解这些过程，从而为伤口愈合和生长相关疾病设计新的治疗方法？在过去的5年里，我一直在回答这些问题。我特别关注了机械力在这些过程中的作用。越来越多的证据表明，机械力可以对细胞的生长产生巨大的影响。例如，宇航员在太空中开始失去骨量，因为没有来自重力的机械张力来刺激骨骼的形成。尽管我们周围有大量证据表明组织的机械环境对其生长非常重要，但在组织水平上对此进行调查的工作却很少。我的CDA研究的一个关键发现是揭示了一种新的方式，即组织缓冲它们所经历的不断波动的力，以保持它们正确的组织形状。我们发现，肌动蛋白和肌凝蛋白是体内重要的蛋白质，为细胞和组织提供结构，当它们受到外部拉伸力时，它们会在一个新的方向上对齐。这加强了组织，并防止组织中的任何切口被撕裂，就像降落伞的加固织物一样。CDA的另一项发现是发现了一种新的伤口愈合机制。正常情况下，组织中的细胞紧密地粘在一起，以维持组织的结构。然而，在受伤后，细胞开始相互移动，并“流入”受伤部位的孔中。我们称这一过程为增加组织流动性，就像液体中的分子相互流动一样。我们表明，通过增加组织的流动性，即细胞可以轻松地相互移动，我们可以提高伤口愈合的速度。上述2个项目最近在高影响力期刊上发表，但还有许多其他项目的进展受到延误。这主要是因为我在CDA期间休了2次产假，第2次休假刚刚回来工作。在我最后一次产假期间，我试图确保实验室研究的连续性，但不可避免的是，动力减弱了，进展变慢了，因为我同时要照顾一个新生儿的需要。因此，现在从生理和心理上都不可能申请高级研究金。如果我能有额外的18个月来准备我的申请，并提供关键的初步数据来加强我的高级奖学金申请，那么这将导致申请的竞争力下降。我需要专注于发表我的CDA中剩余的论文，其中一些为高级奖学金提供了关键数据。由于我在CDA上的产假延期并没有增加人员和消耗品成本，所以我目前没有足够的资金来支持我的员工，他们需要以最有效的方式完成和发表剩余的论文。由于基金申请的缓慢转变，如果没有一些即时的过渡支持，我将失去所有现有的实验室成员，这将对我努力建立的实验室产生巨大的不利影响，我将失去更多的动力，这将进一步降低我成功获得高级奖学金的机会。我相信18个月的时间足以让我发表剩下的关键论文，为Senior Fellowship收集足够的初步数据，最重要的是，恢复我的动力和创造力，写一篇我相信会成功的Senior Fellowship。

As we develop, how do our tissues and organs know when to stop growing when they reach the correct size and shape? How do they then maintain this correct size and shape throughout the rest of adulthood? If they are damaged by injury, how do they heal themselves again to restore their size and shape? Mis-regulation of these processes can lead to overgrowth diseases such as cancer and keloidal scars. Can we understand these processes from a new perspective in order to design new therapies for wound healing and growth related diseases?These are the questions I have been answering with my CDA fellowship over the last 5 years. In particular, I have focused on the role of mechanical forces in these processes. There is increasing evidence that mechanical forces can have a huge impact on the growth of cells. For example, astronauts in space start to lose their bone mass, because there is no mechanical tension from gravity to stimulate bone formation. Despite the large amount of evidence around us that a tissue's mechanical environment is very important for its growth, little work has been done to investigate this at the tissue level.One key finding from my CDA research has been in revealing a new way in which tissues buffer the constant fluctuation of forces that they experience in order to maintain their correct tissue shape. We showed that actin and myosin, important proteins in the body that provide cells and tissue with their structure, align themselves in a new direction when they experience external stretching forces. This strengthens the tissue, and prevents any cuts in the tissue from ripping throughout, much like the strengthened fabric of a parachute. Another finding from the CDA has been the discovery of a new mechanism to heal wounds. Normally cells in a tissue stick together tightly, to maintain the structure of the tissue. However, after injury, cells start to move relative to each other, and 'flow' into the hole at the injured site. We call this process increased tissue fluidity, much like how the molecules in a fluid flow past each other. We show that by increasing the fluidity of a tissue, i.e. the ease in which cells can move past each other, we can increase the rate of wound healing.The above 2 projects have recently been published in high impact journals, but there are many other projects that have suffered delays in their progress. This is mainly because I have taken 2 periods of maternity leave during my CDA, and I have just returned to work from my 2nd leave. During my last maternity leave, I tried to ensure the continuity of my lab's research, but inevitably, momentum has been reduced, and progress slower, as I simultaneously attend to the needs of a newborn. It would thus be physically and mentally impossible to apply for a Senior Fellowship now. It would result in an application that is less competitive than if I could have an extra 18 months to prepare my application and produce key preliminary data to strengthen my Senior Fellowship application.I need to focus on publishing the remaining papers from my CDA, some of which provide critical data for Senior Fellowships. As my maternity extension on my CDA did not extend staff and consumable costs, I am currently running out of funds to support my staff, who are needed to finish and publish the remaining papers in the most efficient way. Due to the slow turn around of grant applications, without some immediate transition support, I would lose all my current lab members, which would have a massive detrimental effect on the lab that I have worked so hard to build, and I would lose even more momentum, which would further reduce my chances of successfully obtaining a Senior Fellowship. I believe 18 months is sufficient for me to publish the remaining key papers, gather enough preliminary data for the Senior Fellowship, and most importantly, regain my momentum and creativity, to write a Senior Fellowship that I am confident will be successful.