The role of PCKalpha and modulation of desmosomal adhesion in delayed wound healing in the elderly

Wounds to the skin do not always heal quickly and over time can lead to disability, distress, or even death, and huge health care costs. This problem is increasing as we have more people in the elderly at-risk age-group, but we do not yet fully understand why older people have poor healing. Skin wounds heal through a complex series of events, which are carefully regulated and involve several cell types. Our group have shown that the female hormone estrogen has a beneficial effect on healing, and acts upon all of the different cell types in a wound. Our understanding of the effects of age on the upper skin layer (the epidermis) and reformation of the outer skin barrier is particularly poor. Recent studies from our laboratory, comparing how wounds from old and young subjects heal, have identified cell adhesion in this upper skin layer (conferred by specialised structures called desmosomes) as a key process that leads to poor healing in the elderly. Furthermore, we have shown that desmosomes undergo specific changes after the skin is wounded. These new studies are essential to answer a number of important questions including how these changes are regulated and the implications for improving delayed healing in the elderly. Our work will initially use cultured cells and mice modified to express desmosomal proteins to understand the biology. This will direct experiments on human samples that will ultimately lead to the development of new treatments to accelerate healing in the elderly.

Non-healing wound states (eg. venous ulcers, diabetic ulcers and pressure sores) impose an immense financial burden on Health Services, and lead to significant patient morbidity and mortality. Increased age and the associated reduction in systemic hormones are clear risk factors for delayed acute wound healing and development of chronic non-healing wounds. Our group have shown that delayed wound healing occurs as result of defects in multiple cell and tissue types and can be reversed by estrogen treatment in both animals and humans. In recent years we have documented a role for dermal changes, including increased and attenuated inflammation, increased protease activity and increased matrix deposition in the delayed healing phenotype. The essential process of re-epithelialisation is also dramatically altered in age-associated delayed healing, yet the underlying cellular and molecular correlates are poorly understood. Our preliminary microarray studies have identified changes in the expression of a large group of functionally related proteins in delayed healing wounds from both mouse and human ? components of the desmosome epidermal adhesion junction. Moreover, we have demonstrated both in in vitro and in vivo that upon wounding desmosomes undergo a unique alteration in calcium dependence that propagates out from the wound, and appears to be mediated by the alpha isoform of protein kinase C. This study will focus on the role of desmosome-mediated epidermal adhesion in age-associated delayed wound healing with data generated used to develop therapeutic strategies to accelerate healing in the elderly. Project aims are:

1) To investigate changes in size, number, biochemical composition and ultrastructural morphology of desmosomes in aged human skin and ovariectomised mice, and understand the contribution of these changes to delayed healing.
2) To determine the influence of PCKalpha on desmosomal function and cutaneous wound healing in vivo, and understand how PCKalpha interacts with desmosomes.
3) To determine the role of desmosomes and PCKalpha in the pathogenesis of human chronic wounds.