NIHRDataInsights/HRCSData huggingface dataset:
Title: Targeting glycans for the treatment of ischemia-reperfusion injury.
Funder: Medical Research Council

Abstract: Mannose Receptor (MR, CD206) has not been widely investigated as clinical target due to the lack of molecular probes able to selectively modulate its activity in vivo, and represents a novel biological target for the treatment/prevention of IRI. We have developed an initial family of novel synthetic glycopolymers (GPs) that bind MR with high affinity and protect against IRI in vivo. In the proposed research we will investigate the mechanism(s) by which GPs are protective in IRI by a combination of in vitro and in vivo approaches as a means to determine the contribution of MR to IRI. Accordingly, key research objectives will be: 1) Generation of MR-binding GPs. A library of MR-binding GPs will be engineered by a combination of controlled/living radical polymerisation (CRP) and Cu-catalysed azide-alkyne cycloaddition (CuAAC) with variable macromolecular size. This will allow to systematically modulate affinity to MR and pharmacokinetic profile, with the aim of establishing structure-function relationship for this novel class of biomaterials within the context of renal IRI. 2) Identify the mechanism by which MR-specific GPs mediate protection against renal IRI in vivo. At this stage we will establish (a) how the macromolecular structure of GPs affects their ability to attenuate IRI; (b) whether GPs can act as both prophylactic agents to prevent IRI and therapeutics to minimise tissue damage following ischaemia/reperfusion; (c) how GPs affect the evolution of IRI vs. time, providing key information on their mechanism of action; and (d) what cells are targeted by GPs in vivo, and how they are involved in the development of reperfusion injury. 3) Establish the effect of MR-specific GPs on the biology and activation of macrophages. Here we will investigate how MR-binding GPs modulate (a) macrophage migration, (b) polarisation, or (c) activation in vitro using primary mouse macrophages.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: MICA: RIP1 kinase inhibition to reduce kidney injury
Funder: Medical Research Council

Abstract: Importance Acute kidney injury (AKI) is a major health problem affecting 2000 patients per million per year in the UK. In addition, ischemic injury to kidneys associated with partial nephrectomy, transplantation vascular and cardiac surgery contributes significant mortality and morbidity. No active pharmacological agent is currently in use to reduce AKI. Solution Regulation of inflammation and cell death and survival pathways is a crucial determinant of cell fate in response to injury. Necroptosis is a newly recognized, regulated form of necrosis, which contributes to kidney injury in renal injury and transplantation. Receptor-interacting protein-1 kinase (RIPK1) has emerged as a kinase with strategic importance in directing cell fate toward necroptosis. This project is testing two inhibitors of RIPK1 in order to reduce kidney damage and improve kidney function as well as survival following renal IRI. Objectives 1. Determine efficacy of RIPK1 inhibitors in human/murine cell-based models of renal injury. 2. Determine protective effect from renal IRI in RIPK1-kinase dead (RIPK1-KD) mice compared with wild-type (RIPK1-WT) mice and determine if RIPK1 inhibition abrogates renal injury. 3. Determine evidence for expression and activation of RIPK1 in human acute kidney injury. Research plan Cell culture experiments will determine RIP1K phosphorylation after injury and define dose response curves of RIP1K inhibitors. Renal ischemia reperfusion injury in RIPK1-KD mice and RIP1K-WT mice will establish whether inactivation of RIPK1 results in renal protection. RIPK1 inhibitors and necrostatin will be used in both RIPK1-KD and RIPK1-WT mice to demonstrate potential non-RIPK1 effects. The extent RIPK1 inhibitors influence other pathways will be determined by transcriptome analysis. RIPK1 expression and phosphorylation will be explored in human kidney tissue.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Androgens: unlocking the key drivers of male health and wellbeing
Funder: Medical Research Council

Abstract: Male health and wellbeing is androgen dependent. This Programme Grant will address the multifaceted challenges relating to the fundamental understanding of the development and maintenance of an optimal androgen profile throughout life, as the best protection for lifelong health, and seek to develop therapeutic strategies to support endogenous/restorative health for men. We will use a combination of mouse models, and primary human cell culture systems. 1. We will establish the origin of two recently identified adult Leydig cell populations and determine their roles. 2. We will determine how Sertoli cells control adult Leydig cell development and function, and pursue key factors as potential therapeutic targets. 3. We will determine the mechanisms by which androgens, and other paracrine factors drive Leydig cell maturation and manipulate these to support healthy androgen profiles. 4. We will generate models of cell-specific premature ageing, to determine the impacts of ageing on the androgen production machinery of the testis, and how this can be abrogated. 5. We will elucidate how obesity and diabetes impact Leydig cell function, characterizing the mechanisms by which metabolic hormones suppress testicular androgen production and identify approaches to overcome this. 6. We will develop a novel lentiviral gene therapy system to establish gene function in promotion of Leydig cell function, and validate this as a gene therapy vector to support/improve Leydig cells. 7. We will generate novel cell-specific ablation models to identify endogenous pathways that can be activated to induce Leydig cell apoptosis and regeneration of a new, youthful Leydig cell population. 8. We will validate cell transplantation as a mechanism to induce new Leydig cell development. This will provide a detailed understanding of the mechanisms underpinning a healthy lifelong androgen profile, and unlock the potential of the testicular 'androgen factory' to support lifelong male health


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: RENAL AND UROGENITAL
Title: Map-based Visualisation and Statistical Inference with Dynamic Health Data
Funder: Medical Research Council

Abstract: The primary aim of the research is to develop the statistical and informatics methodology required for real-time health atlases; as an exemplar it will use primary care electronic health records (SIR) from the population of Salford city and focus on chronic kidney disease (CKD). This will extend the current static health atlases to real-time web applications which will be available in two forms; a 'public' web application will be aimed at the general public and a more sophisticated 'professional' web application will be made available to professionals (subject to data owner's permission). To achieve this statistical methodology will be developed along with open-source software for: querying SIR (SQL); statistical modelling (R-package); and interactively conveying the results via web applications (JavaScript) adhering to established human-computer interaction principles. The software will be flexible enough for the atlas, beyond the lifetime of the project, to be used for other diseases and in different locations. Furthermore it may inform future research projects or health care authorities if unexpected (spatial and/or temporal) disease patterns emerge. The secondary aim is to train the Fellow so that she can make a career transition from physics to biostatistics and informatics. Formal statistics training will realised by her undertaking an MSc in statistics with a bias towards medical statistics and training in informatics will be via directed reading and short courses at the Farr Institute. The MSc project will give the Fellow additional experience of applying advanced statistical methods in a clinical setting; aim is to identify key risk-factors underlying chronic kidney disease progression to end-stage (outcome). Existing statistical methodology will suffice for modelling single time-to-event outcomes but joint modelling of multivariate time-to-event outcomes will require some novel methodological extension.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: RENAL AND UROGENITAL
Title: REGULATORY CASCADES UNDERLYING KIDNEY DEVELOPMENT, HOMEOSTASIS AND DISEASE
Funder: Medical Research Council

Abstract: We propose to use a combination of genome wide approaches to identify WT1 target genes and mRNAs and to determine whether loss or gain of WT1 function influences the transcription, splicing, turnover and translation of these targets. We will determine whether the 2 major WT1 isoforms differing by only 3 amino acids inserted between 2 zinc fingers bind to different or the same targets and function at different steps in the regulatory cascade. We will focus on 2 kidney stages most relevant to human disease that arise through WT1 mutation- the fetal metanephric mesenchyme and adult podocytes. We will identify WT1 binding target genes and RNAs in these two cell types using ChIP seq and CLASH respectively. This will also map the binding sites and identify consensus binding sequences within the RNA. We will then determine whether WT1 regulates these genes and mRNAs and at what levels, including transcription, splicing, transport, translation and turnover. These studies will be carried out in cell lines or tissues having gained or lost WT1 function or its specific isoforms. To measure transcription rates of target genes in these cells we will use polII ChIP seq. To evaluate splicing, transport and target RNA turnover RNA seq will be carried out on fractionated nuclei and cytoplasm from these cells. Translation rates of target mRNAs will be determined using ribosome profiling. Bioinformatics analysis will tell us: what target genes and mRNAs are regulated by WT1 in mesenchyme and podocytes. At what steps does WT1 regulate the expression of its target genes- transcription, splicing, transport, translation, turnover? Does it chaperone some genes throughout the whole regulatory cascade? What is the role of the two major isoforms? What is the role of ncRNA WT1 targets? What are the biological pathways being regulated and how does this inform on the normal biology and diseases of the kidney? Functional experiments will be carried out to validate the findings.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Androgens and women's health: developing new therapies to treat endometrial disorders
Funder: Medical Research Council

Abstract: Endometriosis is a chronic, hormone-dependent, inflammatory disorder characterized by growth of endometrial tissue outside the uterine cavity; it affects 1.5 million women in the UK. The pathophysiology of endometriosis is complex and new personalized therapies to treat the chronic pain suffered by patients is needed. There is compelling evidence that androgens have an impact on the pathophysiology of endometriosis. We have shown that endometrium and endometriosis lesions have AR+ cells and that the treatment of human primary cells, or mice, with androgens has an impact on processes implicated in establishment of these lesions (proliferation, cell migration, tissue remodelling). Androgens regulate inflammatory and pain pathways and the synthetic androgen, Danazol, has been successfully used to treat women with endometriosis-associated pain. Danazol is no longer recommended as a front-line therapy because of unacceptable (virilizing) side effects. However the development of a new class of drug - the selective androgen receptor modulators (SARMs) - tested in women for other indications provides us with the unique opportunity to repurpose SARMs as a treatment of endometriosis-associated pain. The programme will use discovery and translational science to develop a fully rounded understanding of the androgen 'steroidome' of women with endometriosis and the androgen microenvironment of endometriotic lesions. We will stratify responses to SARMs using 3D culture systems (primary human cells) and a mouse model of menstruation (inflammation, progenitor recruitment, repair processes) to prioritise one SARM for testing in our innovative mouse model of endometriosis. The programme will support a wide range of collaborations as well as capacity building in steroids and women's health research by training students and postdoctoral scientists.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL
Title: Investigating the renal microvasculature in polycystic kidney disease
Funder: Medical Research Council

Abstract: Aims and Objectives: Our aims will be to (i) determine whether gene therapy for VEGFC can treat a autosomal dominant PKD model; (ii) determine the mechanisms underlying VEGFC's effect in PKD. Methodology: VEGFC will be administered in a model of autosomal dominant PKD by a gene therapy strategy using adeno-associated viruses. We will use a combination of histological and non-invasive imaging to assess the renal microvasculature. We will use transgenic technology to examine whether there are intrinsic defects in kidney endothelia in PKD. In addition, vascular cells lacking PKD genes will be isolated and their biology and gene expression (using RNA-sequencing) assessed. Finally, a 3-dimensional cell culture model will be used to examine if VEGFC directly modulates cystogenesis. Scientific and Medical Opportunities: This project will enhance our knowledge of renal blood vessels in healthy and polycystic kidneys. In addition, it could lead to the design of new therapies for human renal disease. If this is the case then this will have potential impact on society by improving the quality of life of patients with kidney disease as well as a major economic impact by reducing the number of expensive dialysis regimens or the need for a kidney transplant.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL
Title: Chronic Kidney Disease of unknown cause (CKDu) in disadvantaged communities in low-and-middle income countries (LMICs)
Funder: Medical Research Council

Abstract: There is an increasing recognition of epidemics of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low-and-middle income countries (LMICs). It is currently not possible to determine if the condition has similar characteristics or similar causes in different parts of the world. International comparisons are made more difficult because CKDu is usually clinically silent until it has progressed to advanced stages, so the diagnosis must be made by testing asymptomatic individuals. There is a critical need for a more comprehensive and integrated approach to this problem, involving standardized validation, prevalence and risk factor studies, including comparisons between and within tropical/subtropical regions of the world. We have recently established a collaboration involving a practical protocol to estimate distributions of renal function in disadvantaged communities: the Disadvantaged populations estimated glomerular filtration rate (eGFR) epidemiology study (DEGREE). This will provide key information to inform hypotheses and to guide further research into the causes of CKDu. The Foundation Grant involves undertaking the DEGREE project in four centres (India, Malawi, Peru, Mexico) in three regions (South Asia, Latin America, Sub-Saharan Africa) where the disease is likely to be endemic. In each centre we will conduct a prevalence and risk factor survey in an urban and a rural area (the exception is Mexico where an urban survey is not possible because of the security situation), and we will also undertake a validation study to refine our approach to estimate GFR for cross-population comparisons.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: Trans-national cohorts of nephrotic syndrome - a unified approach to a global chronic disease
Funder: Medical Research Council

Abstract: Kidney disease in LMICs is under recognised and severely under resourced. The incidence of one of the commonest types of renal disease (in adults and children), idiopathic nephrotic syndrome (INS), appears considerably higher in LMICs than in the developed world. This is likely contributed to by a combination of infectious triggers and genetic background, though other factors remain unknown. The biological understanding of glomerular disease has been revolutionised recently by study of the glomerular podocyte, the target cell in INS, alongside significant genetic advances. The field is ripe for translational research on wider patient cohorts to exploit compelling biological hypotheses arising from this work. This proposal brings together researchers with complementary strengths, and will enable knowledge transfer between all partners. The host laboratory in the UK is a world leader in podocyte biology and INS population genetics, and has well-established links with key leaders in nephrology in several LMICs. In the UK we established a national renal patient registry (www.rarerenal.org) and biorepository, with widespread clinician and patient buy-in that is recognised as innovative. We propose to extend this concept internationally, to build a vibrant and cohesive network of academic centre leads in three LMICs with the UK centre as a hub. The downstream benefits will be (i) establish a team of LMIC centres consistently trained in laboratory research/diagnostic techniques and clinical database/biobank establishment (ii) a pipeline to transfer cutting edge translational biology advances from the UK laboratory (and elsewhere) to establish novel biomarker assays locally (iii) share clinical trials methodology that will maximise impact of biomarker findings in large cohorts of patients. Links to Bristol will facilitate definitive studies on genomics, transcriptomics, and epigenetics in this carefully phenotyped population, with on going sustainable skills development


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: RENAL AND UROGENITAL
Title: Personalised management of atypical haemolytic uraemic syndrome
Funder: Medical Research Council

Abstract: Haemolytic uraemic syndrome is a thrombotic microangiopathy (TMA) characterised by the clinical triad of thrombocytopenia, microangiopathic haemolytic anaemia, & acute renal failure. The most common form of HUS is associated with a preceding diarrhoeal illness caused by verocytotoxin-producing bacteria, typically Escherichia coli O157:H7. Those not preceded by this infection are classified as atypical HUS (aHUS) (OMIM 235400). Work undertaken in Newcastle first identified the role of complement in aHUS with ~50% of cases carrying mutations in the complement system. This work ultimately resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. More recently, I have established a dichotomy in response to eculizumab, with a group of patients that do not respond. I hypothesise that not all aHUS is complement driven and that by identifying individuals who will not respond to complement inhibition we will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway complement blockade. The patients will be classified into responders and non-responder groups and the adequacy of complement inhibition measured using in house complement haemolytic assays. Whole exome sequencing will be undertaken in those who do not respond despite complete complement inhibition. Using this method I have already identified 3 novel genes associated with aHUS. Where required in vitro analysis will be performed to confirm the functional significance of these rare genetic variants. I will then measure a series of aHUS related biomarkers to establish a predictive marker of eculizumab non-response. I will then confirm the lack of response to complement inhibition in an in vitro cell model of aHUS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL
Title: MICA: Signalling pathways to proteinuria - part II. Establishment of b3 integrin and TRPC6 as tractable renal disease targets
Funder: Medical Research Council

Abstract: The leading cause of acquired established renal failure (ERF) in children is Steroid Resistant Nephrotic Syndrome (SRNS). This devastating disease usually leads to ERF despite the use of prolonged and toxic immunosuppression. The rapid recurrence of disease (within hours) in transplanted patients has contributed to the 'circulating factor hypothesis' acting via unknown receptor(s) to dysregulate the kidney podocyte. Our observations shed light on novel disease mechanisms linking the activation of protease receptors, especially PAR-1, which signal to the podocyte cytoskeleton resulting in changes in podocyte motility and functional breakdown. We have shown with existing MRC funding that transgenic expression of constitutively active PAR-1 on podocytes (pod-PAR-1active) results in dramatic proteinuria and a phenocopy of severe SRNS. Excitingly, biopsy samples from human SRNS corroborate increased expression of activated PAR-1. In vitro studies reveal a signalling 'platform' downstream of PAR-1, comprising the podocyte specific protein podocin, VASP, TRPC6 and b3 integrin. The latter two are highly attractive targets for clinical therapy with novel compounds. We now wish to demonstrate a direct role for TRPC6 and b3 integrin in mediating PAR-1 mediated proteinuria, so that specific compounds can be tested in vivo. We will achieve this by: (1) Continuing current work to cross the pod-PAR-1active mouse with a pod-TRPC6 knockout mouse, to attenuate proteinuria. (2) Cross the pod-PAR-1active mouse with a podocyte specific b3 integrin deleted mouse, to attenuate proteinuria. (3) Correlate these findings utilising a national patient cohort with SRNS, to investigate active PAR-1 on podocytes in biopsy specimens, thus for the first time stratify patients with 'circulating factor disease'. (4) Test specific inhibitors of b3 integrin and TRPC6 using our model, in a collaboration with industry partners, to deliver rationalisation for clinical trials in this population


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RENAL AND UROGENITAL