Role of microRNA-214 in the control of skin regeneration

Biological mechanisms that regulate the development of mammals, including humans, continue during the lifespan of individuals and are altered during ageing. As an organ that covers the body, the skin protects us from a variety of environmental insults, such as mechanical injury, ultraviolet irradiation, and variations in temperature.

The skin also provides a unique system for studying the mechanisms that control organ development, regeneration and ageing. Skin development results in formation of the epidermis, a stratified self-renewing epithelium. Additional structures of the skin include hair follicles, nails and glands. After birth, the epidermis continuously regenerates using the ability of epithelial stem cells to supply progeny cells that form all epidermal cell layers. Meanwhile, epidermal regeneration, following skin injury, is controlled by stem cells derived from the hair follicle.

Data obtained during the last decade has revealed that many cellular signalling pathways controlling skin development and its postnatal regeneration are of particular importance. Recent data demonstrate that activity of these signalling pathways is governed by microRNAs (miRNAs). These are small ribonucleic acid molecules, which negatively regulate gene expression by interaction with their multiple targets in a sequence-specific manner.

This project will look at how one of those miRNAs, namely miR-214, impacts skin regeneration during normal development and when induced by injury. This project will also explore how miR-214 affects different molecular signals in epithelial stem cells and their progenies (that form skin and hair follicle epithelium), and its involvement in wound healing.

Studying the skin as a model system in this way, will cast light on the mechanisms that control the development and regeneration of other epithelial tissues, such as the epithelia of the intestine, teeth, kidney and lung. The knowledge gained from this study will also provide new opportunities for the development of novel microRNA-based therapies to cure aberrant tissue growth and regenerative conditions.

Skin development and regeneration are governed by complex programmes of gene expression activation and silencing. Recent data demonstrate that activity of many genes implicated in the control of skin homeostasis is regulated by miRNAs, which represent a new regulatory layer during execution of tissue-specific differentiation programmes.

This project will investigate the role of miR-214 in the control of stem cells and their lineage-committed progenies during skin postnatal regeneration and wound healing. Our preliminary work has demonstrated the role of miR-214 in regulating the activity of the Wnt/beta-catenin signalling pathway in keratinocytes and showed that doxycycline-inducible miR-214 (K14-rtTA/TRE-miR-214) transgenic mice develop a skin phenotype (markedly decreased number of hair follicles and delayed onset of hair follicle growth phase) that strikingly resembles the phenotype of beta-catenin knockout mice.

We will test the hypothesis that miR-214 is involved in the control of skin regeneration by regulating the activity of Wnt signalling and cell cycle-associated machinery in epithelial stem cells and their lineage-committed progenies. This hypothesis will be addressed via two specific aims: 1) to define how modulation of miR-214 levels affects proliferation, differentiation and gene expression programmes in epithelial stem cells and their lineage-committed progenies during skin development and physiological regeneration; 2) to delineate the role of miR-214 in the control of injury-associated gene expression programmes in epithelial stem cells and their progenies during wound healing.

Outputs from this project will provide new important insights into fundamental mechanisms that regulate stem cell activity and cell fate decision inside and outside of the skin, and will be highly important for the development of novel miRNA-based approaches for rapidly developing areas of regenerative medicine and stem cell-based therapy.

An understanding of biological mechanisms regulating mammalian development is highly important for better understanding the changes that occur later in life, and affect the health status and longevity of individuals.

This project will look at how miR-214, a member of the small ribonucleic acid molecule family (microRNAs) that negatively regulates gene expression by interaction with their multiple targets in a sequence-specific manner, impacts skin and hair follicle growth, regeneration and wound healing. This project will also explore how miR-214 affects different signalling pathways in cells that form the epidermis and hair follicle epithelium.

SCIENTIFIC COMMUNITY
This project will provide substantial new knowledge for the scientific community and will contribute to an advance in public health benefits.
Delineating the functions of miR-214 in the control of stem cells and their lineage-committed progenies during skin postnatal regeneration, and wound healing will help to advance knowledge for investigators working in the following areas of fundamental research (developmental biology, molecular biology, stem cell biology and tissue regeneration, hair follicle biology), in addition to clinical (dermatology, regenerative medicine) and veterinary medicine.

PUBLIC HEALTH & AWARENESS
This project will have significant health implications and will benefit the public sector, including health professionals and their patients. Chronic wounds represent a substantial public health problem. In the UK, chronic wounds affect approximately 200,000 patients, with an estimated 3% of the annual healthcare budget spent on chronic wound care alone. The information generated by this project will provide new opportunities for therapeutic interventions to cure chronic epithelial wounds. It will also influence the generation of new therapeutics for specific forms of hair loss. This will ultimately contribute to the enhancement of quality of life.

INDUSTRY
Business/industry will benefit from this project by expanding our understanding of molecular mechanisms that control skin and hair regeneration. This is vital for development of new approaches to improve diagnosis and for treatment of skin and hair disorders, leading to substantial economical benefits in related life science industries.

Knowledge transfer activities with the industrial partners will be actively implemented for those areas of the results that can be used for new therapeutic product development. The newly generated knowledge will also be used in the relevant higher education courses for basic scientists and health professionals.

To ensure that the results of the proposed project will be made available to the general public and to the specific groups mentioned above, several approaches will be pursued. The results will be presented at prestigious international conferences. In April 2012, we organised an International Symposium "Epigenetic Control of Skin Development and Regeneration" (http://www.skin.brad.ac.uk/SkinEpigenetics-2012/), which we aim to hold annually. This symposium represents a unique opportunity to bring skin biologists together with scientists studying epigenetic regulatory mechanisms and provides platform for establishing intradisciplinary collaboration.
Our data will be published in international peer-reviewed journals with the widest possible audience. Information on the project outcomes will also be made available to relevant Health and Wound-healing charities.

Overall, this project will provide information of strategic importance for researchers, the business/industrial sector, and health professionals within the NHS, whilst longer term will contribute to better public health.