Considering climate change in the development of marine protected areas

Marine ecosystems are facing a diverse range of threats, including climate change, prompting international efforts to safeguard marine biodiversity through the use of spatial management measures. Marine Protected Areas (MPAs) have been implemented as a conservation tool throughout the world, but their usefulness and effectiveness is strongly related to climate change. However, few MPA programmes have directly considered climate change in the design, management or monitoring of an MPA network. Under international obligations, EU, UK and national targets, Scotland has developed an MPA network that aims to protect marine biodiversity and contribute to the vision of a clean, healthy and productive marine environment. This is the first study to critically analyse the Scottish MPA process and highlight areas which may be improved upon in further iterations of the network in the context of climate change. Initially, a critical review of the Scottish MPA process considered how ecological principles for MPA network design were incorporated into the process, how stakeholder perceptions were considered and crucially what consideration was given to the influence of climate change on the eventual effectiveness of the network. The results indicated that to make a meaningful contribution to marine biodiversity protection for Europe the Scottish MPA network should: i) fully adopt best practice ecological principles ii) ensure effective protection and iii) explicitly consider climate change in the management, monitoring and future iterations of the network. However, this review also highlighted the difficulties of incorporating considerations of climate change into an already complex process. A series of international case studies from British Columbia, Canada; central California, USA; the Great Barrier Reef, Australia and the Hauraki Gulf, New Zealand, were then conducted to investigate perceptions of how climate change has been considered in the design, implementation, management and monitoring of MPAs. The key lessons from this study included: i) strictly protected marine reserves are considered essential for climate change resilience and will be necessary as scientific reference sites to understand climate change effects ii) adaptive management of MPA networks is important but hard to implement iii) strictly protected reserves managed as ecosystems are the best option for an uncertain future. This work provides new insights into the policy and practical challenges MPA managers face under climate change scenarios. Based on the Scottish and international studies, the need to facilitate clear communication between academics, policy makers and stakeholders was recognised in order to progress MPA policy delivery and to ensure decisions were jointly formed and acceptable. A Delphi technique was used to develop a series of recommendations for considering climate change in Scotland’s MPA process. The Delphi participant panel was selected for their knowledge of the Scottish MPA process and included stakeholders, policy makers and academics with expertise in MPA research. The results from the first round of the Delphi technique suggested that differing views of success would likely influence opinions regarding required management of MPAs, and in turn, the data requirements to support management action decisions. The second round of the Delphi technique explored this further and indicated that there was a fundamental dichotomy in panellists’ views of a successful MPA network depending upon whether they believed the MPAs should be strictly protected or allow for sustainable use. A third, focus group round of the Delphi Technique developed a feature-based management scenario matrix to aid in deciding upon management actions in light of changes occurring in the MPA network. This thesis highlights that if the Scottish MPA network is to fulfil objectives of conservation and restoration, the implications of climate change for the design, management and monitoring of the network must be considered. In particular, there needs to be a greater focus on: i) incorporating ecological principles that directly address climate change ii) effective protection that builds resilience of the marine and linked social environment iii) developing a focused, strong and adaptable monitoring framework iv) ensuring mechanisms for adaptive management.

Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.