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

MRC 过渡支持奖：靶向 miR-29 改善伤口基质

基本信息

批准号：
MR/X023397/1
负责人：
Svitlana Kurinna
金额：
$ 31.2万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX023397%2F1
关键词：
MRC Transition Support Award Targeting

项目摘要

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.

团契目的的摘要：在我们的社会中，需要改善其他器官和组织的皮肤愈合和修复的需求不断增加。为了制定有效的策略来改善这些策略，必须了解正常和受损的康复的基础机制。对于我的项目，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的调节剂，称为表皮。受伤后，表皮细胞负责用新的皮肤覆盖伤口部位，以保护我们的身体免受感染的进入和水分流失。了解如何在正常皮肤中调节这一过程，然后在伤口愈合受损的患者中如何减轻这种再生管制。这项研究的总体目标是使用miR-29增强伤口内部细胞的正常生长，我发现这是正常皮肤生长的精确和生理调节剂。 MiR-29已经在诊所中尝试了皮肤硬化症患者的皮肤状况（由皮肤异常增厚表现），因此可能会迅速用于其他皮肤疾病（包括伤口）的分子治疗。但是，它需要知道所有可能与伤口床内miR-29相互作用的分子。为了研究这一点，我使用的是在非治疗手术（例如，整形手术）以及人伤口的活检和伤口愈合模型的活检后，使用了剩余的人类皮肤活检的细胞。我发现MIR-29的抑制作用通过增强角质形成细胞的附着和成纤维细胞的生长更快，这是伤口基质内的另一种主要细胞类型，从而改善了伤口愈合。此外，我的小组已经发现了一种新的机制来改善伤口内血管形成，主要是通过miR-29介导的内皮细胞的分子变化，这些内皮细胞正在皮肤中的血管内衬。 MRC过渡支持奖学金将使我能够研究miR-29对成纤维细胞的生长和细胞外基质沉积的影响，以及内皮细胞在伤口中血管形成的确切机制。我将使用简短的合成核酸分子来改变miR-29的水平，这将铺平皮肤成功再生的新策略的发展。该项目的长期目标是利用miR-29来改善患有大型急性伤口，创伤，卧床和糖尿病性溃疡的患者的皮肤再生。如何推进我的职业：我的目标是申请MRC高级奖学金。尽管我已经建立了一个新的研究方向，但我需要更多的出版物才能使我在高级奖学金中竞争。过渡资金将使我能够保留在小组中接受过培训的博士后研究员，因此在两年过渡期间促进了另外两篇论文的出版。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。对于我的博士后，这种支持也将非常重要，后者打算建立她的独立研究生涯。