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Corneal dystrophies

Understanding the relationship between proteases and protein aggregation in corneal dystrophies

The Danish Council for Independent Research | Medical Sciences - Grant: DKK 6,463.411

Project Period: 01.08.2014 - 30.07.2018

Background

Worldwide, an estimated 285 million people suffer from visual impairment of which 39 million are blind (World Health Organization, 2012). The global health costs of visual impairment and blindness were estimated to be $3 trillion in 2010 (Gordois A, et al., 2012). Despite treatment options, onset of blindness cannot be prohibited because the pathogenesis of many eye diseases remains poorly understood.

The cornea is avascular and sequestered from the immune system. It can be divided into five layers (i). the epithelial layer (ii), Bowman’s layer (iii), stromal layer (iv), Descemet’s membrane, and (v), the endothelial layer. Numerous diseases manifest as protein deposits within specific layers of the cornea as in lattice corneal dystrophy (LCD) and granular corneal dystrophy (GCD), and Fuchs’ endothelium corneal dystrophy. Corneal dystrophies embrace a heterogeneous group of inherited diseases manifesting within one or more of the corneal layers. They are typically bilateral, symmetric, and progress slowly. The age of onset for corneal dystrophies ranges from early childhood to adulthood depending on the dystrophy variant (Klintworth GK, 2009).

Aim

Corneal dystrophies are a group of inherited protein misfolding diseases. The aim of this project is to identify drug targets and new therapeutic modalities for non-invasive treatment of these devastating eye diseases. Preliminary data suggests that corneal proteases are valid targets for therapeutic intervention. The function of proteases is diverse, however the regulation of protein turnover both inside and outside the cells is well documented. Proteolysis is of paramount importance to biological regulation, and its significance is magnified because it is irreversible. Imbalance in proteolytic activity can thus have dramatic consequences and is important to the pathology of virtually every type of human disease including, infection, inflammation, thrombosis, cancer, emphysema, neurological degeneration, etc. Thus, the obtained knowledge of protease involvement in corneal dystrophies may impact other studies where proteolysis is involved.

For more information on corneal related research conducted in the laboratory of professor Jan J. Enghild, please visit our website: enghild-lab.dk


List of participants in the project

  • Professor Jan J. Enghild (MBG and iNANO)
  • Postdoc NN (to be employed)
  • PhD student NN (to be employed)
  • Laboratory Manager Ida B. Thøgersen (MBG)

 

Collaborators

  • Professor Jesper Hjortdal (Aarhus University Hospital)
  • Professor Henrik Vorum (Allborg University Hospital)
  • Professor Hideaki Nagase (University of Oxford, UK)
  • Professor F. Xavier Gomis-Ruth (Molecular Biology Institute of Barcelona, Spain (CSIC))
  • Professor Simon J. Conway (Indiana University, School of Medicine)
  • Dr. Kang Zhang (UC San Diego Health Center, USA)
  • Professor Eung K. Kim (Yonsei University College of Medicine, Seoul, Korea)

The project also included Dr. Gordon K. Klintworth (Duke University, NC, USA), however, Dr. Klintworth sadly passed away in 2014, after spending more than 50 years in the field of research.