NIHRDataInsights/HRCSData huggingface dataset:
Title: Transition Support CDA Raman Das
Funder: Medical Research Council

Abstract: Differentiating neurons in the developing spinal cord undergo acute loss of apical polarity through the process of apical abscission. The nascent neuron must now rapidly re-establish polarity to determine the correct position of axon outgrowth, leading to formation of functional neural circuitry. My fellowship aims to study the molecular and cell biological mechanisms that direct the important process of neuron repolarisation using cutting-edge methods to image spinal cord neurogenesis in real time at high spatial and temporal resolution in ex-vivo tissue slices. With my MRC CDA-funded postdoc, I have established the role of the primary cilium during neuronal differentiation. Briefly, we have uncovered a novel cell biological mechanism, called primary cilium remodelling, that leads to a switch in the cellular response to Sonic Hedgehog (Shh) signalling, which now directs correct axon extension. This work has been published at Science Advances, and directly leads to two further novel lines of investigation that will produce two strategic publications and set up my long-term research programme as a tenured academic: Objective 1: Determine the mechanisms directing polarised microtubule rearrangements. Objective 2: Determine the mechanisms of non-canonical Shh signal transduction. This work will uncover the novel mechanisms through which neurons translate extracellular signalling cues to achieve the polarised cytoskeletal rearrangements characteristic of axon extension and will consolidate the research niche I have established. Furthermore this work will directly lead on to the objectives of my senior fellowship, which are to investigate the mechanisms of primary cilium remodelling and how this allows cells to dynamically translate and integrate the diverse extracellular signalling cues that direct the stepwise process of neuron polarisation


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Systematic Reviews and Meta-Analysis of Prognosis Studies (REVAMP): development of core methods, reporting guidelines and a methodology handbook
Funder: Medical Research Council

Abstract: Precision medicine relies heavily on prognosis research findings, which allow health professionals to understand and predict outcomes in patients with a particular disease or condition. The PROGRESS framework defines four types of prognosis research: (i) overall prognosis, (ii) prognostic factors, (iii) prognostic models and (iv) predictors of treatment effect. The implementation of prognosis research findings should be evidence-based, with multiple high-quality studies confirming their accuracy and reliability. This motivates the need for systematic reviews and meta-analyses of prognosis studies to identify, critically appraise, synthesise and summarise the evidence. Although guidance is well developed for reviews of intervention studies, the methodology for prognosis reviews is only just emerging, and is especially sparse for overall prognosis and predictors of treatment effect. Yet prognosis reviews are rapidly being undertaken, as seen from living reviews of COVID-19 prognosis studies. Hence, there is an urgent need to develop robust methods and guidance to support those undertaking prognosis reviews, including Cochrane, Evidence Based Medicine centres, and decision makers such as NICE. Our grant will address this via five work packages (WPs), covering step-by-step guidance for reviews of overall prognosis (WP1); reporting guidelines for types (i) to (iii) (WP2); equations for appraising the sample size of prognostic model studies for risk of bias classifications (e.g. to ascertain overfitting concerns) (WP3); methods to improve risk of bias and meta-analysis in reviews of predictors of treatment effect (WP4); and sample size calculations for new prognosis studies that subsequently will be included in an updated review (WP5). Our findings will be disseminated in a Handbook for Prognosis Reviews (co-written with Cochrane Prognosis Methods Group), a UK-based training course, journal articles, statistical software, and tutorials at www.prognosisresearch.com.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: New adaptive platform designs for clinical trials in an emerging disease epidemic
Funder: Medical Research Council

Abstract: Adaptive designs include interim analyses, at which a clinical trial may be stopped or modified, without inflating the type I error rate. One adaptive design of recent interest is a platform trial, which assesses multiple experimental treatments with the ability to add further treatments into the study or drop those that are ineffective. Such designs have been recommended by WHO and NIHR for evaluation COVID-19 treatments, and are being used in ongoing trials, allowing newly-proposed therapies to be tested as quickly as possible. Although adaptive platform trial designs offer valuable flexibility, given the considerable uncertainty regarding disease progression and patient numbers in an epidemic of a new disease, it is desirable to make clinical trials even more flexible. This is shown by ongoing COVID-19 trials in which the maximum number of patients to be included and duration of the trial, the number of experimental treatments and when these will be available, and the primary endpoint that will be used to evaluate treatment effectiveness, have all been left unspecified. With this flexibility some ongoing trials can only approximately control type I error rates. This project will develop new statistical methodology to allow the desired flexibility whilst maintaining the scientific integrity of the trial by ensuring control of the type I error rate. Specifically, we will develop methods that allow the maximum sample size and the number and timing of treatments to be added to the trial to be unspecified and allow the trial primary endpoint to be changed. Research findings will be disseminated via a workshop where we will obtain input from a wide range of methodological and clinical colleagues to facilitate implementation. Consensus will sought where possible and areas of remaining controversy identified. We will also produce a webinar to explain and raise awareness of platform trials to stakeholders including patients and the general public.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the benefits and burdens of funding processes, from idea to award.
Funder: Medical Research Council

Abstract: The cost of developing, writing, reviewing and deciding on research proposals is an under-researched but critical prerequisite to understanding the efficiency of funding decisions. This has recently become a priority issue for the UK Government, who recently published a policy paper on 'Reducing bureaucratic burden in research, innovation and higher education', which included a commitment to work "with external advisers to provide additional, independent challenge and to calculate the total costs of bureaucracy". The primary aim of the project is to estimate the monetised costs of the peer review process for a sample of grant schemes, and to balance that against the value that is derived from the process, for the applicants, reviewers, panel members and Research Council staff. A secondary aim is to develop a toolkit that will allow UKRI, and other research funders, to assess the cost and value of other peer review processes in the future. To deliver on these two key aims a mixed method approach of data collection and analysis will be employed including process mapping, surveys, interviews, cost modelling and policy analysis. Data on burdens and benefits will be collected through a series of surveys administered to applicants, peer reviewers and panel members and through key informant interviews with UKRI staff and university research office staff. The data will be analysed through rigorous and appropriate methods using SPSS and NVivo (or similar packages). The results of the quantitative and qualitative analysis will be synthesised to draw out estimates of the benefits and burdens of peer review processes, and examined by source of benefit/burden and each stage of decision making, as well as assessing the degree of commonality or difference across funding schemes. The results will be written up for publication in peer reviewed journals along with message led policy briefs and a practical cost modelling toolkit for the funder community.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Structures of full-length FGFR cancer fusions and disease mutants
Funder: Medical Research Council

Abstract: This 3-year project grant will combine and integrate insights from an array of advanced experimental techniques, including cryo-EM, cross-linking-MS, and methyl-resolved NMR, to effect a step change in our structural understanding and knowledge of functional interactions of FGFRs, and of RTKs more broadly. Specifically, building on prior work and recent progress in our labs, we are well placed to make a major advance towards high-resolution structures of full-length RTKs by exploiting our combined expertise in FGFR signalling biology, functional protein reagent generation and analysis, and cutting-edge structural biology tools and infrastructure. Levering these assets, we are poised to understand better how FGFRs and their most common and important disease-altered forms (including gene fusions with TACC proteins) are activated and transduce signals. We will address the following previously intractable research questions: - What conformations do RTK intracellular domains assume in intact (full-length) membrane-embedded RTKs and how do these change in response to activation status (e.g. phosphoforms) and to extracellular domain conformation and ligand-bound status? - How do the conformational changes induced by C-terminal oncogenic gene fusions including FGFR3-TACC3 lead to hyperactivation and interactions with altered cellular networks, and do these changes in turn present new opportunities for fusion-selective targeting?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Proteolytic activation of calcium channels: potential target for channel - directed therapeutics in arterial smooth muscle cells
Funder: Medical Research Council

Abstract: The a2d1 subunits are key to the function of L-type Voltage-Gated Calcium channels (Cav1.2) in the regulation of cardiac contraction, vascular tone, and neuronal excitability. Abnormal Cav1.2 currents in arterial Smooth Muscle Cells (SMCs) are a hallmark of hypertension, but the involvement of a2d1 in the pathogenesis remain elusive. Despite their pathological relevance, the molecular mechanisms underlying Cav1.2 regulation by a2d1 are poorly understood. I will pursue multidisciplinary approach by applying biochemical, imaging, optical and electrophysiological techniques to investigate the molecular basis of the regulation of Cav1.2 by a2d1 subunits. I will focus on a novel post-translational mechanism for control of the biological functions of a2d1 determined by the enzymatic cleavage into disulfide - linked alpha2 (a2) and delta (d) moieties. I will undertake detailed structure-function analysis of the molecular properties of the linker domain between a2 and d (named proteolytic domain a2d-PD) that are of key importance for the biological functions of a2d1, and for the regulation by post-translational cleavage. I will build on my collaboration with crystallography experts in UCL to obtain the structure of the a2d-PD peptide. I will assess the efficacy of synthetic peptides based on a2d-PD to act as novel Cav1.2 channels - directed inhibitors by supressing a2d1 cleavage. I will investigate the implications of targeting this pathway for the regulation of a2d1 in arterial Smooth Muscle Cells (SMCs), and as a potential route for development of novel Cav1.2 channels - directed therapeutics to reduce vascular resistance. I will use an optical approach named Voltage Clamp - Fluorometry to obtain structural evidence of how voltage-sensing properties of Cav1.2 are controlled by the cleavage of a2d-PD in live cells. The research will benefit from collaborations with experts in ion channel research in UCL, UCLA and in my host department of SGUL.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural biology of chromosome folding and dysregulation in disease
Funder: Medical Research Council

Abstract: The cohesin complex is a multisubunit, dynamic molecular machine comprised of four core subunits, SMC1, SMC3, SCC1 and SA1/2 as well as a number of regulatory factors that are required for DNA loading and translocation (SCC2/SCC4), to stabilise cohesin on DNA (PDS5 and ESCO1 acetylation) and that enable cohesin release (WAPL). The long-term goal is to understand the molecular mechanism by which cohesin entraps DNA and catalyses loop extrusion and that allows cohesin deployment in a number of important genome transactions. We have recently determined structures of a series of cohesin subcomplexes, mostly using xray crystallography. To understand how accessory factors control cohesin function one needs to capture the complex in defined compositional and conformational states. We here propose to use a structural, biochemical and cell biological biology approach to better understand the structures of larger cohesin complexes bound to different accessory factors. We will also create and test defined mutations (in vitro and vivo) for effects on biological function. The different protein subunits of the cohesin complex are mutated in many 'Cohesinopathies' that range from cancer to developmental disorders. More specifically, cohesin dysregulation during meiosis in oocytes can lead to mis-segregation of chromosomes resulting in cells with the wrong number of chromosomes, a hallmark of Down's syndrome (Trisomy 21) and is a leading cause of age-related aneuploidy and infertility. Mutations in the cohesin complex are associated with genetic diseases such as Cornelia de Lange and Roberts syndrome which result in severe development defects. Cohesin mutations also can result in genomic instability due to mis-processing of chromosome loops, dysregulation of chromosome replication, repair or segregation. Our work will form the basis for a more detailed understanding of cohesin function and dysregulation in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Genetic Evaluation of Multimorbidity towards INdividualisation of Interventions (GEMINI)
Funder: Medical Research Council

Abstract: We will test the hypothesis that there are unrecognised combinations of long term conditions (LTCs) which arise due to shared biological pathways, and that these can be discovered using human genetic methods. Recent studies indicate that this is an exciting and feasible approach to advance the understanding of multimorbidity, with human genetic and genomic data leading to new discoveries about shared mechanisms between LTCs. Our research is divided into three complementary work packages (WPs). In WP1, we will select LTCs that are common and use genetics to identify those that are likely to share biological pathways. We will use data from three primary care databases consisting of millions of patients to identify LTCs present in >1% of people aged >65 yrs. We will then use data from large (10,000s of cases) genetic studies to identify LTCs that are genetically correlated with each other. In WP2, we will identify some of the specific mechanisms underlying the LTC combinations identified in WP1. We will test if known modifiable risk factors, such as BMI, account for some of the genetic correlations. We will then use more specific sets of genetic variants to identify potential causes. These genetic variants will include those representing genes expressed in specific cell types, those representing potential drug targets, and those that can be used in Mendelian randomization tests of specific risk factors. We will develop new methods to ensure our causal inferences are robust, including the use of genetic variants to test whether one condition causes a second condition. In WP3, we will obtain patients' perspectives on the new LTC combinations. We will then use the primary care datasets to test the hypothesis that the new LTC combinations represent distinct clinical entities, defined as patients aged >40 yrs with >1 condition having worse outcomes than expected. Our results will inform future translational studies aiming to reduce the burden of multimorbidity


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploiting a novel molecular toolkit to explore cell type specific adenosine receptor pharmacology and regulation at endogenous levels of expression.
Funder: Medical Research Council

Abstract: The urgent need to understand how adenosine receptors are regulated and organised in their local cellular environment is illustrated by recent studies that show that G protein coupled receptor (GPCR) expression in a given cell type is highly heterogenous and that the receptor repertoire of an individual cell can change dramatically during disease progression. We have combined medicinal chemistry, molecular pharmacology and physiology to develop ground-breaking fluorescent ligand technologies to interrogate endogenous GPCR molecular pharmacology at the single cell level and in ex vivo cardiovascular tissues. These include development of novel suites of fluorescent ligands together with the application of super-resolution microscopy, fluorescence correlation spectroscopy, genome-editing, nanobodies, NanoBRET and ligand-directed covalent labelling of receptors with fluorescent tags. Initial proof of concept work with each of these approaches initially was in recombinant cells lines expressing the target receptor of interest. However, in recent years our focus has been to develop highly subtype selective fluorescent ligands (agonists and antagonists), ligand-directed covalent tagging strategies and to utilise CRISPR/Cas9 genome-editing and NanoBiT-conjugated nanobodies to tag receptors at endogenous levels of expression. In this new programme of work, we will apply these approaches to study adenosine receptor pharmacology, oligomerisation and the influence of protein-protein interactions on adenosine receptor signalling and location in different cell types and tissues. Furthermore, the use of pluripotent stem cell technologies, and the ability to differentiate cells into different phenotypes (from cardiomyocytes, fibroblasts and endothelial cell to neurones), provides a fantastic platform to use our new imaging technologies to investigate the impact of local cellular environment on GPCR signalling which should have wide-ranging implications for drug discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Establishing a structure-function relationship between biomolecular condensates and protein degradation
Funder: Medical Research Council

Abstract: The dynamics and physical attributes of biomolecular condensates (BMs) are closely linked with their biological roles. Condensation and dissolution in response to stress is a hallmark of stress granules, whereas the conversion from liquid-like to gel-like states of p62 bodies can result in degradation via autophagosome formation. These processes are tightly regulated through two main mechanisms: 1) via post-translational modifications or 2) by changing the BM composition, specifically of the non-scaffold components (ligands). Determining how ligands affect phase boundaries within live cells is crucial for understanding how BM formation occurs in the right place at the right time. Here we propose to design novel biomolecules that can alter the physical properties of BMs and to introduce these engineered molecules into a cell model to understand how changes in the physico-chemical properties (characterised in vitro) affect the targeted degradation of liquid droplets via autophagy in the complex cellular environment. To achieve our goals, we will: 1) create novel proteins comprising molecular adhesive peptides to drive liquid-liquid-phase separation (LLPS) and a consensus tetratricopeptide repeat protein (CTPR) to endow the droplets with functional capabilities, 2) characterise LLPS in vitro to define how ligand recruitment modulates the physico-chemical properties of the LLPS-CTPRs, 3) relate the properties of the LLPS-CTPRs to autophagosome formation and subsequent protein degradation, and lastly, 4) explore the design of LLPS-CTPRs as a therapeutic strategy to enhance substrate degradation or dissipation of natural occurring BMs. Using this systematic approach, we will establish a structure-function relationship between BMs and protein degradation, ultimately enabling us to rationally design novel biomolecules that can enhance targeted degradation of disease-related proteins.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Effective population adjustment in evidence synthesis of randomised controlled trials for health technology assessment
Funder: Medical Research Council

Abstract: Background: Multilevel network meta-regression (ML-NMR) is a recently proposed framework for combining individual patient data (IPD) and aggregate data from multiple randomised controlled trials (RCTs) on different treatments, adjusting for population differences to produce population-adjusted estimates in target populations for decision-making. However, there are several barriers to the use of ML-NMR for decision-making in practice. In particular i) the need for methods that work well in situations where data availability is limited, and ii) the need to address common issues in the analysis of RCTs such as missing data, non-compliance, and treatment switching. Aims and Objectives: This research will address these issues through novel methodological developments and recommendations to improve the evidence base, to ensure that ML-NMR can be effectively and widely utilised to make efficient, population-targeted treatment decisions. Methods: This will be achieved by: WP1 Developing novel ML-NMR methods to utilise additional information reported by RCTs, aiding estimation with limited or no IPD. WP2 Performing simulation studies to explore the performance of the methods developed in WP1 as the amount of data available becomes limited. WP3 Investigating the availability of additional information in trial reports; developing recommended updates to reporting guidelines via a stakeholder workshop. WP4 Developing methods to adjust for common issues in the analysis of RCTs within the ML-NMR framework. WP5 Producing accessible software tools and short course training in the proposed methods. Opportunities: Availability of enhanced statistical methods, software, and reporting guidelines will have direct impact for decision makers such as NICE, leading to better informed treatment decisions in technology appraisals and clinical guidelines. There are direct applications in personalised medicine, where recommendations are targeted to individuals or smaller groups.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE