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

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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.