Uncovering TOR signaling as evolutionary conserved pathway in wound healing and skin damage responses

10/26/2016

Of fly, mouse and man - the research team led by Sabine Eming, Dermatologist at the Univ. Hospital of Cologne and Principal Investigator at the CMMC and CECAD Cologne, identified unique functions of target of rapamycin (TOR) signaling in skin morphogenesis and epidermal barrier formation.

In multicellular organisms the primary function of the skin is to protect the organism from environmental stress factors such as injury, microbes, toxic substances, and to maintain its integrity. Therefore, by nature the skin is explicitly well furnished to restore tissue function and homeostasis following tissue damage. Consistently, there is strong evidence for evolutionary conserved repair programs that restore skin integrity after injury. Several of the previously uncovered, evolutionary conserved repair genes have been identified as critical regulators of the wound healing response in humans.

In patients multiple conditions can impair the skin’s regenerative capacity, and among those the aging process is one of the most common and important. Increased skin fragility, metabolic dysfunction, and chronic wounds are leading causes of increasing morbidity and mortality in the elderly. Current strategies for preventing or treating age-related skin pathologies are insufficient.

“The underlying molecular and cellular mechanisms how aging factors compromise skin function are elusive and a better understanding is critical for the development of efficient approaches to intervene in aging-associated decline of skin function”, says Sabine Eming.

Research groups around the world, particularly also Cologne-based scientists, contributed to the recent discovery that altering the activity of components of the TOR pathway at the systemic level, can extend healthy life-span in laboratory animals. This effect is conserved in evolution and can be studied in diverse laboratory model organisms including Drosophila and the mouse.

Some years ago the Eming group posed the question by which mechanisms TOR-mediated longevity controls skin-specific ageing mechanisms and what might be the specific role of TOR at the systemic and/or the cellular level in skin. To pursue her hypothesis Sabine Eming teamed up with the groups of Linda Partridge, Director of the Max Planck Institute for Biology of Ageing, and Maria Leptin, Professor at the Institute of Genetics of the University of Cologne.

“The idea was that using in parallel the fly, mouse and human to investigate the role of TOR in skin development and repair responses might offer an effective approach to open up new avenues to obtain unique insights and developing novel strategies geared toward rejuvenation of the skin and attenuating aging-associated skin diseases”, explains Sabine Eming. Recent findings now show that this complementary and collaborative approach was successful.

Xiaolei Ding, the first author of the study, disrupted individual components of the mTOR pathway in mice by conditional gene targeting. Collectively, he provided genetic evidence for a fundamental role of mTOR signaling in the formation and maintenance of a protective epidermal barrier. “We discovered distinct functions for mTOR complex 1 and mTOR complex 2 in skin barrier formation, which cannot compensate for each other. “Our findings unravel important and novel mechanistic insights in TOR-mediated epidermal development, maintenance and disease” he states.

”We aim to continue this complementary analysis to dissect now the mechanisms underlying TOR-mediated activities in skin maintenance. In addition, studies have been initiated to understand how these findings in model organisms can help to identify clinically relevant wound healing genes. Studying tissue damage responses and aging in such a collaborative environment provides a fantastic opportunity for exploiting one of the most promising approaches for delaying age-related pathologies for therapeutic options in skin diseases”, concludes Eming.


Original Publication:
Xiaolei Ding, Wilhelm Bloch W, Sandra Iden S, Markus A. Rüegg, Michael N. Hall, Maria Leptin, Linda Partridge, Sabine A. Eming.
mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation.
Nature Communications 2016


CMMC-Reseach Project - C9
Mechanisms regulating age-associated decline of skin regenerative capacity
Sabine Eming and Maria Leptin

 

Contact:
Prof. Dr. med. Sabine A. Eming
Dermatology and CMMC
University of Cologne
Kerpenerstr. 62
50937 Cologne
sabine.eming@uni-koeln.de

http://www.eming.uni-koeln.de/Sabine_Eming_Research_Group_-_Uni_Koln/Sabine_Eming_-_Uni_Koln.html

Epidermal morphogenesis in mTORC1 mutants is severely impaired. Switch-off from the simple epithelial keratins K8/18 towards K14 expression is delayed and maintenance of periderm is prolonged in Rap <sup>EKO</sup> mutants

The Eming Research Team