In ANCA-associated vasculitis (AAV), the body's own white blood cells attack blood vessels. The kidneys are most commonly involved in AAV, frequently leading to kidney failure and dialysis. Amongst people that require dialysis, 2-3 out of 10 do not survive, and 4 out of 10 do not recover kidney function. Importantly, infection and heart disease are leading causes of death. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression. Whilst prognosis has significantly improved, there remains significant risk of damage from the disease and its treatment, especially during the first 12 months. Cytomegalovirus (CMV) is a common virus, present in over half the population. After initial infection, the virus remains in the body for life and undergoes periods of reactivation. In a healthy person, the immune system keeps the virus under control. Recent research within my supervisors' group, showed that asymptomatic CMV reactivation occurs in roughly 1 in 4 people with stable AAV and leads to expansions of harmful immune cells able to damage blood vessels. We know that CMV reactivation and expansion of these harmful cells are associated with reduced kidney function and increased risk of infection and heart disease. What we do not yet know is how often asymptomatic CMV reactivation occurs in patients with newly diagnosed or recently relapsed AAV. We anticipate that CMV will reactivate much more frequently during the first 12 months following diagnosis or relapse (the acute phase), due to the medication needed to suppress the immune system and inflammation from the vasculitis, and that this will be linked with worse outcomes. We also do not yet know how CMV reactivation may amplify the damage that vasculitis can do to the kidney. Our preliminary work suggests that CMV reactivation increases the proportion of a specific inflammatory group of white blood cells called monocytes (CCR2 expressing monocytes) in AAV. Our preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis. The main aims of this study are to measure the frequency of CMV reactivation during the first 12 months and determine whether this is linked to increased disease activity, ongoing dialysis requirement and increased damage from AAV. We will then explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV. We will aim to recruit all patients with newly diagnosed or recently relapsed AAV. Patients will be followed up with 10 study visits over 12 months. At each visit, participants will be required to give blood and urine samples to determine if CMV has reactivated and measure other inflammatory chemicals and proteins. Participants will also be asked to fill in a questionnaire on their health and quality of life. A kidney biopsy is performed routinely to confirm a diagnosis of AAV. We will use some of this kidney tissue to identify the number of monocytes in the tissue and assess if this is related to the kidney damage we see on the biopsy. If our current proposed study confirms that CMV reactivation is common during acute AAV and is linked with significant complications, this may lead to future research of suppression of CMV in a trial, aiming to improve outcomes for people with AAV. This research will also improve our understanding of the importance of CMV in driving kidney damage which may be relevant to other kidney conditions.

Some radioactive molecules emit gamma radiation that can be detected outside the body and so when injected into humans and animals, in safe low levels, can be used to generate images, using sophisticated scanners, of the brain for biomedical research and clinical diagnosis. However, the molecules have to be designed to target the sites of the brain to be investigated, which is done by attaching a biological compound to the radioactive molecule to create products called radiopharmaceuticals. Due to the severe lack of scientists in the UK who have the specialised skills to design and prepare these radiopharmaceuticals we plan to recruit and train a scientist to join our multidisplicinary team. To achieve this we have created a bespoke training programme which will involve learning from researchers in academia and industry, who are either developing and/or using this imaging technology. As part of this training the scientist will help design new radiopharmaceuticals that would then be used in our on-going research programmes to understand the biological mechanisms of some major diseases and disorders of the brain, and thereby identify some possible treatments. For this specific programme we would be undertaking research projects on traumatic brain injury, depression, schizophrenia, obsessive compulsive disorder and drug addiction.

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds. Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems. The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.

Chiral amines are prevalent in natural products, which often display potent biological activity. Such chiral amine motifs are also frequently found in pharmaceutical drug compounds and chemical building blocks meaning that the development of environmentally benign and sustainable routes to produce these important motifs is extremely desirable. Nature synthesizes these complex and valuable molecules through the action of highly specialized enzymes. These natural catalysts enable an extremely efficient biosynthesis from simple starting materials, installing functional groups with exceptional levels of selectivity. Chemical catalysts are frequently designed to mimic the action of enzymes and are often capable of achieving impressive selectivity. However, unlike enzymes, processes involving these catalysts usually involve high temperatures, sub-optimal pH, organic solvent and complex purification methods. Enzymes called omega-transaminases (TAs) catalyze the conversion of commercially available or easily accessible starting materials to high-value amines. These biocatalysts require an additional donor molecule to provide the amine functional group. This donor is ultimately converted to a by-product and the desired amine product is formed. However, the reaction is freely reversible and unless this by-product is removed from the reaction, low yields of the desired amine will be isolated, as the enzyme will more readily catalyse the reverse reaction to regenerate starting materials. A number of elegant approaches have been reported which remove this ketone by-product and allow access to appreciable quantities of the chiral amine. These strategies include the addition of expensive enzymes or the use of extremely large quantities of the amine donor in combination with the technically challenging removal of ketone by-products. One such approach, which relies on an extensively modified TA, is currently used for the industrial synthesis of the antidiabetic drug compound, sitagliptin. However, the approach is far from efficient and the development of this heavily modified TA biocatalyst was enormously challenging, highlighting an immediate need for more sustainable strategies for performing these biotransformations and for developing suitable enzyme catalysts. This research will build upon recent work reported in our laboratory that describes arguably the most efficient approach to date for performing biotransformations involving TAs. The success of the approach is due to spontaneous precipitation of the by-product, which cannot regenerate starting materials. This polymer is also highly colored and has allowed the development of an effective high-throughput screening strategy that enables the rapid identification of active enzymes. Our focus now is to optimize the process further and make it more suitable for industrial application. Specifically, low cost amine donor molecules will be used that are spontaneously removed from the reaction in a similar way to our previously reported method. We will also apply a simple high-throughput screening strategy to assist in the genetic engineering of natural enzymes in order to increase the scope of the reactions that they can catalyze and make them suitable for industrial scale synthesis. The enzymes developed in this study will enable cost-effective, sustainable and environmentally neutral methods for the small/medium and industrial scale production of one of the most important compound classes.

Stratified Medicine is a type of personalised medicine where treatments are directed specifically at people who are most likely to respond to them, often using detailed information about individuals. We believe that the treatment of patients with hepatitis C virus (HCV) would benefit enormously from this approach. About 300,000 people in the UK are infected with HCV, only half of whom have been diagnosed as carrying the virus. The virus has a high tendency to persist as the body's immune system is usually unable to clear infection. HCV infects the liver, causing liver cirrhosis (scarring), liver failure and liver cancer. HCV exists in different genetic forms called genotypes. In the UK, most infections are caused by either genotype 1 or 3, which occur at about equal frequency. Treatment for HCV has consisted of two drugs interferon and ribavirin. Approximately half of patients receiving treatment respond and are successfully cured of infection. Until recently, no additional drugs were available to treat those who failed treatment. The number of people who develop severe liver disease from HCV is expected to continue to rise over the next two decades. Those who develop liver failure can be given a transplant but the transplanted organ is rapidly infected with the virus and often becomes diseased within a few years. New drugs, which directly act against the virus (called DAAs), are being used in combination with interferon and ribavirin in NHS patients for the first time in the clinic in 2012. DAA drugs increase the cure rate to 70%. However, there are drawbacks: the drugs are very expensive costing in excess of £20,000 per patient; the virus can become resistant to new drugs, rendering them useless and increasing the frequency of resistant strains in the community; the first wave of new drugs are effective against genotype 1 but not genotype 3 strains; additional side effects can be associated with the new drugs, so that treatment may be stopped before the virus is eliminated. We have developed a team of experts in the clinical care of HCV patients, who will work with HCV scientists, in partnership with industry. Combining expertise in this way should serve to benefit patients. The group is already working well together collecting blood samples and information from 10,000 people across the UK into a single bio-bank, supported by government infrastructure. We aim to assess the genetic make up of both the virus and the infected person. We will also look at the way in which the immune system responds to the virus, and measure protein markers in the blood. We will assess these in patients receiving therapy and also in those with serious liver disease to try to work out in advance who will develop further complications of their disease. A unique feature of our group will be the ability to draw all these strands together. We will develop new technologies so that we rapidly obtain the host and viral sequence in thousands of infected people. In this way we hope to improve treatment options for patients so that the right therapies are given to patients who are most likely to benefit from them. We will focus our efforts especially on HCV genotype 3, which is a particular problem in UK patients, and also on patients with more serious liver disease, who are more difficult to treat with the new therapies. Ultimately we hope to predict the likelihood of treatment response in individuals, and possibly through our investigations develop new therapies. This could bring considerable cost-savings to the NHS and means that drugs are given to HCV-infected people who are most likely to respond to them.