MRC Transition Support Award: Targeting miR-29 to improve wound matrix

奖学金目的摘要：在我们的社会中，对改善皮肤愈合和其他器官和组织修复的需求不断增加。为了开发有效的策略来改善这些，必须了解正常和受损愈合的机制。在我的项目中，我正在寻求进一步描述小核糖核酸（RNA）分子miR-29的功能，我将其确定为皮肤顶层（称为表皮）的调节因子。受伤后，表皮细胞负责用新的皮肤层覆盖伤口部位，保护我们的身体免受感染和水分流失。了解这一过程在正常皮肤中是如何调节的，以及这种再生在伤口愈合受损的患者中是如何失调的，这一点非常重要。这项研究的总体目标是利用miR-29促进伤口内细胞的正常生长，我发现miR-29是正常皮肤生长的精确生理调节剂。迄今为止取得的进展：重要的是，由于短RNA的小尺寸和化学性质，miR-29可以用于分子治疗。miR-29已经在临床上尝试用于改善皮肤硬化患者的皮肤状况（表现为异常皮肤增厚），因此可能迅速用于其他皮肤疾病的分子治疗，包括伤口。然而，它需要知道与伤口床内的miR-29相互作用的所有可能的分子。为了研究这一点，我使用了从非治疗性手术后残留的人类皮肤活检中分离出来的细胞（例如，整形手术）以及人伤口的活组织检查和伤口愈合的小鼠模型。我发现，抑制miR-29通过增强角质形成细胞的附着和成纤维细胞（伤口基质内的另一种主要细胞类型）的更快生长来改善伤口愈合。此外，我的团队还发现了一种新的机制来改善伤口内的血管形成，主要是通过miR-29介导的皮肤血管内皮细胞的分子变化。MRC过渡支持奖学金将使我能够研究miR-29对成纤维细胞生长和细胞外基质沉积的影响，以及内皮细胞在伤口中形成血管的确切机制。我将使用短的合成核酸分子来改变miR-29的水平，这将为成功再生皮肤的新策略的发展铺平道路。该项目的长期目标是利用miR-29来改善患有大面积急性伤口、创伤、褥疮和糖尿病溃疡的患者的皮肤再生。过渡资金如何促进我的职业生涯：我的目标是在申请MRC高级奖学金时处于有利地位。虽然我已经建立了一个新的研究方向，我需要更多的出版物，使我有竞争力的高级奖学金。过渡资金将使我能够保留我的博士后研究员，在我的小组训练，从而促进在两年的过渡期内发表另外两篇论文。此外，这将为我提供更大的工作稳定性，因为我将被曼彻斯特大学永久雇用。这种支持也将是一个非常重要的我的博士后，谁打算建立她的独立研究生涯。

Summary of fellowship aims: The need of improved skin healing and repair of other organs and tissues is continuously increasing in our society. For the development of efficient strategies to improve these, it is essential to understand the mechanisms underlying normal and impaired healing. For my project, I am seeking to further describe functions of small ribonucleic acids (RNA) molecules, miR-29, which I identified as regulators of the top layer of the skin called the epidermis. Upon wounding, the cells of the epidermis are responsible for covering the wound site with a new layer of skin that protects our body from infection entry and water loss. It is very important to understand how this process is regulated in the normal skin, and then how this regeneration is deregulated in patients with impaired wound healing. The overall goal of this research is to enhance normal growth of cells inside the wound using miR-29, which I discovered to function as precise and physiologic regulator of normal skin growth.Progress made so far: Importantly, because of the small size and chemical properties of short RNAs, miR-29 can be used for molecular therapy. miR-29 have already been tried in the clinic to improve skin condition in patients with cutaneous sclerosis (manifested by the abnormal skin thickening), and thus can potentially be rapidly used for molecular therapy of other skin diseases, including wounds. However, it requires knowing all possible molecules that interact with miR-29s inside wound bed. To study this, I am using cells isolated from human skin biopsies remaining after non-therapeutic surgeries (e.g., plastic surgery) as well as biopsies of human wounds and mouse model of wound healing. I found that inhibition of miR-29 improves wound healing through the enhanced attachment of keratinocytes and faster growth of fibroblasts, another major cell type inside the wound matrix. Moreover, my group has uncovered a new mechanism to improve blood vessel formation inside the wound, mainly through the miR-29-mediated molecular changes of endothelial cells that are lining the blood vessels in skin. The MRC Transition Support Fellowship will allow me to study the effect of miR-29 on growth and extracellular matrix deposition by fibroblasts, and the exact mechanisms of blood vessels formation in wounds by the endothelial cells. I will use short synthetic nucleic acid molecules to change levels of miR-29, which will pave the development of the new strategy of a successful regeneration of the skin. The long-term goal of the project is to utilize miR-29 to improve skin regeneration in patients suffering from large acute wounds, trauma, bedsores, and diabetic ulcers.How transition funding will advance my career: My aim is to be in a strong position to apply for an MRC Senior Fellowship. Although I have established a new research direction, I need more publications to make me competitive for the senior fellowship. Transition funding will allow me to retain my postdoctoral fellow, trained in my group, therefore facilitating publication of two further papers in the two-year transition period. In addition, it would provide me with greater job stability as I would be employed by the University of Manchester on a permanent basis. This support will also be of a high importance for my postdoc, who intends to establish her independent research career.