- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Investigating the role of cyclin-dependent kinases in the regulation of DNA repair by non-homologous end-joining 27 Apr 2017
DNA double-strand breaks (DSBs) are highly toxic lesions that can drive genome instability and cancer. In human cells, most DSBs are repaired by the non-homologous end joining (NHEJ) pathway, except when they occur during DNA replication or mitosis when NHEJ is toxic and can generate chromosomal translocations. NHEJ must therefore be tightly regulated to maintain genome stability. However, little is understood about how the core NHEJ repair machinery is regulated. PAXX is the last core NHEJ factor to be identified, and may be a substrate for cyclin-dependent kinases (CDKs). A highly conserved residue in PAXX, S148, matches the consensus for phosphorylation by CDK1/2, and preliminary data indicate that it is indeed phosphorylated by these kinases. The aim of my project is to generate human cell lines expressing PAXX-S148 mutants that either prevent or mimic phosphorylation (Ser>Ala or Ser>Glu) on this site and investigate how expression of these PAXX variants impacts on DSB repair. Key goal 1: produce human cell lines expressing wild-type or mutant fluorescent PAXX variants and examine their DSB repair capacity and sensitivity to ionising radiation Key goal 2: investigate when CDK-dependent phosphorylation of PAXX occurs during the cell cycle
This research investigates the relationship between 5-HT neurons and two key brain functions: sleep-wake changes and fear learning. Of particular interest is the role in these processes of glutamate co-released from 5-HT neurons. Two approaches will be used. One approach is based on recent evidence that glutamate is preferentially released from 5-HT neurons firing at low frequencies, whereas 5-HT is preferentially released at higher frequencies. The second approach is based on a mouse with glutamate deficient 5-HT neurons.In Oxford the research will have 3 main goals:i) Measurement of firing of identified 5-HT neurons during the sleep-wake cycle. This will be achieved using optotagging to record for the first time, the firing of identified 5-HT neurons during changes in sleep-wake activity.ii) Optogenetic manipulation of 5-HT neurons on sleep-wake activity. These experiments will optogenetically manipulate 5-HT neurons (using different stimulation frequencies) to establish the causal relationship between changes in 5-HT firing and sleep-wake activity.iii) Optogenetic manipulation of 5-HT neurons in mice with glutamate-deficient 5-HT neurons. These experiments will use a mouse with glutamate-deficient 5-HT neurons to further test the role of glutamate co-release.I will follow a similar research strategy to investigate the role of glutamate co-released from 5-HT neurons in emotional learning at NIH.
Our application provides the platform for a uniquely inter-disciplinary scientific programme linking biomedical, social and health systems research to deliver scientific insights of global importance to human health. We will work based from Kenya (Kilifi and Nairobi) and Eastern Uganda (Mbale). The Kilifi Programme will tighten its focus on our integrated platform (i.e. linked hospital/demographic/molecular surveillance) and legacy of continuous epidemiological data and stored samples over 25 years. Work in Mbale will consolidate a leading centre of clinical investigation in an area of hyper-endemic malaria transmission, and the Nairobi Programme will increase its independence with a focus on international disease mapping and health systems. Our major scientific themes include vaccines (including pre and post-licensing studies with exploratory immunology and epidemiological components), genomics and infectious disease transmission, clinical research (focusing on multi-centre clinical trials and the pathophysiology of critical illness with a developing programme on neonatal and maternal health), public health (with an emphasis on spatio-temporal analyses) and health systems research. The Programme is delivered by 29 PIs (i.e. scientists with independent funding). Training is central to our vision, and additional awards support 18 post-doctoral scientists and a projected 50 PhD students during the next 5 years.
In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research 26 Jan 2016
Efforts surrounding the Millennium Development and Sustainable Development Goals have brought much needed attention to lessening the burden of disease shouldered by women and children, which is most severe in low-income countries. Lasting advances in women’s and children’s health will require improvement of health systems, environment, education, improved access to effective health interventions, including better ways to deliver care in rural, low-income settings. Innovations in each of these areas will require clinical, social science and implementation research. However, many of these women and children are considered to be vulnerable to harms, coercion or exploitation, making inclusion in even potentially beneficial research ethically concerning. While significant strides have been made to develop research ethics guidance for those working with vulnerable populations, critical gaps remain in our understanding of specific vulnerabilities in context, accompanying abilities, the role of social support in mitigating vulnerability, and individuals’ own perceptions of vulnerabilities and abilities. To address these gaps and to improve support and guidance for responsible research with women, children and families, we propose an interdisciplinary collaborative study with investigators in maternal-child health, infectious disease, and social science research across three international sites in the Wellcome Trust Major Overseas Programmes: Kenya, South Africa and Thailand.
What causes major depression? 08 Dec 2015
The objective of this proposal is to discover genetic loci that impact on risk for major depressive disorder (MDD). Our previous Wellcome funded work in China developed a consortium that delivered the first replicated genome-wide significant loci influencing MDD. We now want to take that success forward. Success depends on access to a large, suitably characterized, clinical sample. Of all common diseases, MDD requires most attention to the quality and nature of phenotyping. This is because MDD likely represents a broad neurobiological syndrome with multiple inter-locking etiologic pathways rather than a single disease entity with a clearly defined pathophysiology. We aim to collect 24,000 cases of recurrent major depression and 24,000 screened controls, using a collection strategy that maximizes clinical severity and homogeneity. Together with our existing sample of 12,000, the total sample will be 60,000, sufficent to identify at least 30 genetic risk loci. This will transform our understanding of the origins and nature of MDD, providing a starting point for improvements in mental health care.
Faithful chromosome segregation is essential for the proliferation of all organisms. Although studies in popular model eukaryotes have found that macromolecular kinetochore complexes assemble onto centromeric DNA to facilitate segregation, it is not known whether this mechanism applies to all eukaryotes. To uncover fundamental principles of eukaryotic segregation machinery, I am studying kinetochore functions in Trypanosoma brucei, an evolutionary distant eukaryotic parasite. No kinetochore prot eins has been identified and thus how trypanosomes segregate their chromosomes remains a black box. In my pilot study, I carried out a localization-based screening and proteomics and identified 12 kinetochore proteins. In this proposal, I aim to identify the complete kinetochore proteomes in T. brucei. Identified kinetochore proteins will be characterized using various techniques both in vivo and in vitro to reveal the molecular mechanism of chromosome segregation in trypanosomes. By revealing w hich features are fundamental and which are species-specific, I aim to understand the design principles of kinetochores that facilitate chromosome segregation with exquisite accuracy. Understanding the mechanism of chromosome segregation in trypanosomes is also medically important to develop better treatment for these diseases.
RCT to evaluate an intervention for depressed HIV-positive women in the perinatal period, to enhance child development and reduce maternal depression 02 May 2016
Rates of HIV are very high amongst pregnant women in parts of sub-Saharan Africa (SSA) with, for example rates of over 30% in antenatal clinics in South Africa1. Many receive their diagnosis during pregnancy as partof screening to prevent mother-to-child transmission (PMTCT). Depression is very common amongst these women, with up to 40% screening above the threshold for depression2, 3. Perinatal depression is associatedwith poor adherence to antiretroviral treatment (ART)4, 5, low clinic attendance, suicidal ideation6 and lowrates of breastfeeding7. Of major concern is the evidence of negative effects on fetal outcomes, children'sgrowth and cognitive development7. Improving the wellbeing of mothers and infants requires effectivetreatment of HIV and perinatal depression8. Although treatment of depression improves adherence to HIVtreatment by >80% 5, there is no established effective treatment for perinatal depression in SSA for motherswith HIV. The aim of this study is to develop and test the feasibility and acceptability of a six-session intervention targeting perinatal depression in HIV-positive women. The intervention will utilise Behavioural Activation (BA), which has been shown to be as effective as Cognitive Behaviour Therapy (CBT) in high-income settings9. BA is much simpler than CBT to deliver, especially by non-specialist health workers withlimited training in under-resourced settings. This early phase study is needed to develop, standardise and pilot the BA intervention and test its feasibility. The study will provide treatment for 70 pregnant women and follow them to 3 months postnatally. The outcomes of the main study will include: maternal depression, child emotional and cognitive development and growth, adherence to ART, initiation and maintenance of breastfeeding, infant HIV testing and vaccinations. This work will be conducted at the Africa Centre for Health and Population Studies, a large demographic surveillance site in South Africa with a high HIV prevalence.
The transition to diets rich in meat and dairy is occurring at different rates throughout the world. It is a key driver of the increase in mortality and morbidity associated with diet-related disease and also of the increasing impact of food production on the natural environment. It also has huge cultural and economic significance. It is commonplace today to call for "food system thinking" when considering how diets might be changed to improve heath and sustainability outcomes, but much more rare for this to be put into practice. We shall build an interdisciplinary food system team to show what changes in meat and dairy consumption will provide the greatest health and environment benefits and develop interventions to help bring them about. Our programme will develop innovative global health models, based on novel epidemiological data, to radically improve policy development and provide multiple food system and environmental outputs. In both a developed and developing country setting we shall propose and test novel interventions for healthy and sustainable diets, understanding their interconnectedness and the social and political contexts underlying successful implementation. We shall provide an independent source of evidence to inform debates on meat and dairy.
University of Oxford - Chromosome and Developmental Biology
The role of AMPA receptor calcium permeability in hippocampal interneuron plasticity, circuit 30 Sep 2016
Calcium-permeable AMPA receptors (CP-AMPARs), largely absent from principal cells in adulthood, are highly expressed in several interneuron populations, including hippocampal parvalbumin-positive basket cells (PVBCs). The contribution of CP-AMPARs to PVBC activity, plasticity and subsequently network functions is of great interest, given the role of these cells in hippocampal gamma oscillatory activity, implicated in information maintenance during working memory. However, the contribution of PVBC CP-AMPARs to network dynamics central to gamma oscillation generation, and consequentially effective working memory, hasn’t been established. We aim to look at multiple levels to ascertain the impact of CP-AMPAR manipulations on neural and behavioural function. First, we plan to characterize the effects of CP-AMPAR blocker philanthotoxin-433 on network dynamics and spatial memory. Second, we will selectively delete GluR1 in PV+ cells, resulting in constitutive loss of the primary CPAMPAR contributing subunit, and establish the impact of CP-AMPAR loss at each level. Finally, given that CP-AMPARs are defined by their lack of GluR2 subunit, and that PVBCs do not express GluR2, we aim to artificially overexpress GluR2 in PVBCs using an adenoviral agent in order to remove AMPAR calcium permeability without decreasing overall cellular AMPAR levels, and subsequently fully characterize the impact of this permeable-to-impermeable AMPAR switch.