Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

India

High blood pressure causes an increase in the size of the heart (cardiac hypertrophy) and is a major risk factor for the development of heart failure. One in five people die from this condition. Angiotensin II is a hormone that stimulates cardiac hypertrophy and it functions by binding to the Angiotensin II type I (ATI) receptor. A complex programme of intracellular signalling is initiated to stimulate hypertrophy and a new protein called ATRAP has been recently identified that protects against the effects of Angiotensin II. ATRAP was discovered because it binds to the ATI receptor but how ATRAP suppresses cardiac hypertrophy is not known. We have made an unexpected connection between ATRAP and a lipid binding protein, RdgB-beta. We propose to define the connection between the two proteins, ATRAP and RdgB-beta in the context of lipid signalling via enzymes called phospholipases that produce the 'signalling lipid', phosphatidic acid (PA). We will establish how this protein-lipid network operates during Angiotensin II signalling. The activity of phospholipases is stimulated when Angiotensin II binds to the receptor. RdgB-beta is uncharacterised and we have discovered that it has unusual lipid binding properties - it binds PA. Our concept is that RdgB-beta sequesters the 'PA' signal and therefore restrains the signalling cascade resulting in inhibition of cardiac hypertrophy. We will examine how RdgB-beta binds 'PA' and disposes of it. Because ATRAP binds RdgB-beta we think that a 'bridge' between two membranes is formed. This allows the 'PA' to be removed from the plasma membrane where signalling occurs and sent to the compartment where lipids are re-used for making new lipids. To form the bridge, RdgB-beta has to interact with ATRAP on one membrane and other proteins on the opposite membrane. We will therefore identify these proteins by using RdgB-beta as bait to fish for new proteins. We will also study the importance of RdgB-beta and ATRAP by increasing or decreasing the protein levels in the cells. This will inform us on how Angiotensin II signalling is affected. If RdgB-beta reinforces the restraint put by ATRAP on Angiotensin II signalling, this will provide strong evidence that the molecular mechanism used by ATRAP is to participate in the removal of the signalling lipid, PA. To further test the model, we will delete the gene for RdgB-beta in a model organism (Drosophila) and examine the phenotype in collaboration with our project partner in Bangalore, India. To determine the importance of PA binding to RdgB-beta, we will make mutant proteins that cannot bind PA. These mutants will be examined for rescue of the fly defect. The interaction between RdgB-beta and ATRAP together with the binding of PA to RdgB-beta could provide the molecular explanation of how ATRAP is able to suppress the function of Angiotensin II signalling and could therefore offer a novel therapeutic target for intervention in cardiovascular diseases. In the clinic, inhibition of Angiotensin II signalling by ACE inhibitors that prevents the production of Angiotensin II or drugs that prevent binding of Angiotensin II to its receptor are used for treatment for hypertension. Since most drugs have side-effects, drug combination that targets different systems are often used. Therefore the proposed research could well lead to a different molecular target which could provide a more effective treatment. Understanding how the endogenous inhibitor of Angiotensin II signalling, ATRAP, functions, may provide new strategies for drug targeting. Because ATRAP interacts with RdgB-beta, the possibility that targeting RdgB-beta may provide a unique opportunity to generate a new class of drugs that could be based on binding small hydrophobic molecules in the lipid binding pocket of RdgB-beta. The benefit derived from such drugs is huge as high blood pressure is one of the most common diseases that afflict humans.

The tropics are warming and the frequency of extreme heat events, often accompanied by drought, is increasing across most of the tropical forest biome. It is currently unclear what the effects of increasing heat on tropical forests will be. This key question is the focus of the current IOF proposal, based on three integrated strands of NERC research in Amazonia, which we lead and propose to pilot in India. The approach consists firstly of a targeted real-time observation program at a forest site at the Southern border of the Amazon humid forests, as part of the NERC BIO-RED consortium, co-led by Gloor and Phillips. Real-time observations of forest performance rely heavily on cameras overlooking the canopies, which measure canopy temperatures, measures of productivity performance and stress, and phenology. To characterize the climate forcing, we measure continuously climate and soil humidity. In order to understand observed patterns of tree performance responses to heat extremes, we measure separately traits of the site's dominant tree species related to tree hydraulics, as well as productivity. Secondly, as part of another ongoing NERC grant (TREMOR, led by DG) we are measuring tree hydraulic properties of dominant trees at 10 sites distributed across the Amazon. Knowledge of these characteristics across wide areas permits us to generalize mechanistic results measured with the in-situ monitoring approach. Finally, in both ongoing and past grants OP has developed a tropical forest plot-monitoring network in Amazonia, Africa, and Borneo (~1000 1-ha plots now), capable of tracking longer-term shifts in forest biomass, productivity, and composition. We propose here to work with leading Indian scientists to apply these approaches in this critical region. In large parts of tropical India heat waves have increased considerably in recent years with peak temperatures reaching up to 50C. Model projections suggest that up to 45% of Indian forests may be at risk of shifting to non-forest vegetation states, yet there are only very limited data to evaluate these projections. India lacks both a comprehensive observational system as at our Amazon site, and has relatively few permanent plots, and those that do exist are mostly not integrated into international forest monitoring networks. To address these challenges we have formed new connections with key experts in India covering the areas of forest ecology, eco-physiology, and climatology. Between them our new Indian collaborators are strongly linked to national and international forest conservation efforts, and lead most available forest plots. The scientific focus of this proposal, the extensive, biodiverse and potentially climate-sensitive evergreen forests in Western Ghats, is where the team's interests coincide geographically. We propose to jointly install a canopy-overlooking continuous forest heat and drought-response monitoring site, as in S Amazonia, close to existing plots in the Western Ghats. Together we plan a site-level traits campaign of dominant species and local integration of plot- and canopy-observation monitoring. We further propose to harmonize protocols of plot censuses and to include Indian plot data in the pan-tropical forest census database to support larger scale geographical analyses and syntheses. I-FOR will also aim to support mutual exchange of skills, focused in three steps. The first, in the Western Ghats, is a workshop dedicated to student and young scientist education in field skills and protocols. Secondly, we plan several visits of Indian colleagues to Leeds to support joint analyses and post-project planning. The final workshop, to be hold at one of the Indian scientist's home institution, will include wider participation to discuss implications of the results and to take practical steps toward ensuring these activities become long-term efforts.