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

团契目标摘要：在我们的社会中，对改善皮肤愈合和其他器官和组织的修复的需求不断增加。为了开发有效的策略来改善这些，了解正常和受损愈合的潜在机制是至关重要的。在我的项目中，我试图进一步描述小核糖核酸(RNA)分子miR-29的功能，我认为它是皮肤顶层表皮的调节器。在受伤时，表皮细胞负责用一层新的皮肤覆盖伤口部位，保护我们的身体免受感染、进入和水分流失。了解这一过程在正常皮肤中是如何调节的，然后在伤口愈合受损的患者中如何解除对这种再生的调节是非常重要的。这项研究的总体目标是使用miR-29促进伤口内细胞的正常生长，我发现miR-29可以作为正常皮肤生长的精确和生理调节因子。迄今取得的进展：重要的是，由于短RNA的小尺寸和化学特性，miR-29可以用于分子治疗。MIR-29已经在临床上用于改善皮肤硬化症患者的皮肤状况(表现为皮肤异常增厚)，因此有可能迅速用于包括伤口在内的其他皮肤疾病的分子治疗。然而，这需要了解在伤口床内与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(例如整形手术)后残留的人类皮肤活检组织中分离出来的细胞，以及人类伤口的活检组织和伤口愈合的小鼠模型。我发现，抑制miR-29通过促进角质形成细胞的附着和成纤维细胞的更快生长来促进伤口愈合，成纤维细胞是伤口基质中的另一种主要细胞类型。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介导的内皮细胞的分子变化，这些细胞排列在皮肤的血管内。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，这将为开发成功再生皮肤的新策略铺平道路。该项目的长期目标是利用miR-29改善患有大型急性伤口、创伤、压疮和糖尿病溃疡的患者的皮肤再生。过渡资金将如何促进我的职业生涯：我的目标是在申请MRC高级研究员方面处于有利地位。虽然我已经确定了一个新的研究方向，但我需要更多的出版物来使我在高级研究员职位上具有竞争力。过渡期资金将使我能够留住我的博士后研究员，在我的团队中接受培训，从而促进在两年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，因为我将长期受雇于曼彻斯特大学。这种支持对我的博士后来说也是非常重要的，她打算建立自己的独立研究生涯。

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.