- Total grants
- Total funders
- Total recipients
- Earliest award date
- 01 Nov 2005
- Latest award date
- 10 Apr 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Molecular mechanisms of neural circuit function 28 Nov 2017
I aim to (i) discover molecular and cellular mechanisms that underpin neuronal properties; (ii) elucidate how these properties shape neural circuit activity to generate behaviour. C. elegans offers special opportunities to address these questions. C. elegans kept at 21% O2 adopt a different state from animals kept at 2. We are deconstructing the tonically signalling circuit that coordinates this state change via fast and slow-acting mechanisms. To achieve this, we isolated 583 mutants defective in escape from 21% O2. I propose to elucidate the function of several conserved protein complexes highlighted by these mutants. These include: 1) An interleukin-17 signalling pathway that changes circuit gain; 2) Membrane proteins of unknown function that I speculate promote biogenesis of many ion channels; 3) An ER complex promoting biogenesis of GPCRs; 4) A pan-neuronally expressed calmodulin-binding transcription factor controlling neural excitability. These studies combine genetics, biochemistry and cell biology, and integrate in vivo C. elegans work with studies in mammalian cells. To complement the genetics, we will use RNA-seq of FACS-sorted C. elegans neurons to study circuit plasticity, and adapt a platform developed for pan-neuronal imaging of freely-moving zebrafish larvae to freely-moving C. elegans, to provide a more comprehensive phenotypic readout.
A randomized trial of therapy shortening for minimal tuberculosis with new WHO-recommended doses and FDC drugs in African/indian HIV+/HIV- children. 12 Jun 2013
1) To determine whether treatment of minimal TB disease in children for 4 months results in 18-month disease-free survivalthat is non-inferior to treatment for 6 months, both with standard, but recently increased doses (WHO recommendation) ofanti-TB regimens of isoniazid and rifampicin supplemented by pyrazinamide for the first 2 months and ethambutol in areasof high HIV prevalence.2) To determine via nested PK substudies:a) The plasma PK of Isoniazid, rifampicin and pyrazinamide taken as daily new paediatric fixed-dose dispersible tabletcombinations in African and Indian HIV-infected and uninfected children across different ages according to weight-baseddosing tables. Results would be compared to values following administration of single drugs (within child) and to historicaldata in adults and children.b) To describe the effect of rifampicin on the PK of key antiretroviral drugs (efavirenz at standard doses in children olderthan 3 years; ritonavir-boosted lopinavir (with additional ritonavir boosting), nevirapine in fixed dose combinations withadded neviripine; zidovudine and abacavir in triple nucleoside regimens.c) to evaluate the association between PK and adverse drug effects and to response to anti-TB drugs.d) Using PK modeling, to simulate dosing approaches in different groups of children (race, age, nutritional status, cotreatmentwith ART).
RNA-binding proteins in health and disease. 10 May 2011
Our research focus on the role of RNA-binding proteins (RNABPs) in gene expression at different levels during the RNA processing cascade from splicing in the nucleus to translation in the cytoplasm. RNAs in cells associate with RNABPs to form ribonucleoprotein (RNP) complexes. There is a great variety of RNABPs, each with unique RNA-binding activity giving rise to a unique RNP for each RNA. They have a profound impact on cellular gene expression networks, affecting processes as diverse astranscription, pre-mRNA splicing, microRNA (miRNA) biogenesis and function andtranslation.
The main goal of this project is to investigate the input-output function of single neurons in the ventromedial nucleus of the hypothalamus (VMH), and test whether dendritic computations can contribute to information processing in these neurons, in particular in the circuit that controls aggressive behaviour. There are three initial key questions: (1) How do dendrites in VMH neurons integrate excitatory synaptic input? (2) What is the distribution of excitatory synapses from different inpu t pathways on VMH dendrites? (3) How do VMH neurons integrate information arriving from specific brain areas? These questions will be addressed in actute brain slices, using whole-cell recordings, 2-photon glutamate uncaging, and optogenetics together with calcium imaging. Specific brain regions will be targeted by stereotaxic injections, and axons and synapses visualized with genetic and immunohistochemistry methods. These experiments will be done in the ventrolateral VMH subdivision (VM Hvl), which control aggressive and sexual behaviour, and will identify the repertoire of dendritic computations of the VMHvl, as well as how they might be engaged by activation of specific projection areas. The final goal is to use immediate-early genes and viral tracing of VMH projections to target the neurons involved in aggression, and investigate dendritic information processing in this specific cell population.
Approximately 40% of the world s population is at risk from malaria, and with the increasing prevalence of drug resistance, the need for novel, effective drugs against this pathogen is increasingly urgent. The most virulent form of malaria is caused by waves of replication of the unicellular parasite Plasmodium falciparum within an intraerythrocytic parasitophorous vacuole (PV). At 48-hour intervals, rupture of the infected erythrocyte releases merozoites (a process called egress) which invade f resh erythrocytes to repeat the cycle. Egress is governed by the release of an essential parasite serine protease called SUB1 from maturing merozoites into the PV space. SUB1 initiates a cascade which involves the proteolytic processing of a papain-like enzyme family called SERA. At least two members of this family, SERA5 and SERA6, are essential for parasite viability. SERA5, and likely the other SERAs, is then further processed by another, as yet unidentified protease (which we refer to as the P50C protease). The purpose of this project is to investigate the role of the SERA proteins in parasite egress; verification of the enzymatic activity of the SERAs and identification of their substrates and of the P50C protease will provide new targets for the development of antimalarial drugs.
Music From the Worm Farm. 02 Jul 2008
MUSIC FROM THE WORM FARM will be a six-month research and development residency in the Nurrish Lab within MRC Cell Biology Unit, University College London, exploring a new and experimental collaboration between composer Keith Johnson and neurobiologist Stephen Nurrish. The deep questions at the heart of both our interests are those that concern the brain and the body, what we think and what we do, and the mysterious middle ground between them. The residency will be documented and disseminated via a website; including written and visual material alongside original musical works, and a public presentation.
Wellcome funding will allow the MRC to appoint an extra 5 CRTFs between 2017-2021.
The origin and catabolism of genotoxic aldehydes and their impact on stem cell maintenance. 03 Dec 2014
Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses. 08 Apr 2013
The aryl hydrocarbon receptor (AhR), a ligand dependent transcription factor best known for mediating the toxic effects of xenobiotics, has recently been shown to play important roles in the immune system, although mechanistic insight is lacking. AhR is expressed in a wide range of haematopoietic cells, but also on epithelial cells interfacing with the environment, eg skin, lung, intestine. We plan to investigate the physiological functions of AhR in the immune system by generating AhR-FTAP mice to identify protein interactions with AhR in different cells types and immunological conditions to gain mechanistic insight into how AhR works. Furthermore, we will focus on the physiological regulation of AhR signaling via metabolic enzymes such as CYP1A1 that are induced by AhR activation and subsequently metabolise the agonist in a negative feedback loop. Mice with targeted deletion of the three CYP enzymes under control of AhR show increased AhR stimulation and have a range of immunological phenotypes, which we plan to explore, using infection/inflammation models targeting skin, lung or intestine. AhR deficient mice on the other hand show hyperinflammatory reactions, suggesting that interference with the regulation of AhR activation adversely affect homeostasis at these barrier sites. Analysis of mice with cell type specific AhR deletion will identify cell intrinsic consequences of defective AhR signalling. We furthermore plan to generate mice overexpressing CYP1A1 to test the hyp othesis that rapid degradation of physiological AhR ligands may result in dysregulation of immune responses at mucosal barriers sites.
An examination of the origin and mechanism of formation of the parasitophorous vacuole membrane in erthrocytic stages of the malaria parasite Plasmodium falciparum. 09 Dec 2013
What is the originof the parasitophorous vacuole membrane(PVM) that is producedwhen the malaria parasite, Plasmodium falciparum, invades its host erythrocyte, andwhatare the contributions of host and parasite components, particularly those of the malarialrhoptry organellesininvagination of the erythrocyte membrane and subsequent establishment of thePVM?Thisis a long standing unresolved, question that has not received much attention recentlybut that is a fundamental aspectof Plasmodium biology. Newly developed genetic and imaging technologieswillbe applied that will allow new insight into this question.
Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial. 16 May 2011
The principalresearch question is how best to reduce excess early mortality in African HIV-infected adults andchildren initiating ART. Reasons for high early mortality are multi-factorial, including high rates ofco-infections (TB, bacterial infections, fungal/protozoal infections, parasites), immunereconstitution inflammatory syndrome (IRIS), malnutrition and advanced HIV infection. Severalinterventions might therefore reduce early mortality in HIV-infected patients startingART with low CD4, and could form part of a highly effective integrated care "bundle".