NIHRDataInsights/HRCSData huggingface dataset:
Title: MICA: Exosomes and microRNAs regulate neuro-immune interactions in chronic pain
Funder: Medical Research Council

Abstract: Chronic inflammatory or neuropathic pain remains undertreated as the efficacy of current strategies is limited by severe side effects. Elucidation of specific mechanisms that underlie chronic pain can open new therapeutic avenues. Pre-clinical studies including ours indicate that neuron interactions with immune cells contribute to chronic pain. Our novel evidence indicates that after peripheral nerve injury dorsal root ganglia (DRG) neurons release extracellular vesicles containing microRNA-21 (miR-21), which are engulfed by macrophages where miR-21 promotes a pro-inflammatory phenotype and the release of pro-nociceptive cytokines. As inhibition of miR-21 prevents neuropathic allodynia, we suggest that delivery of miR-21 antagomir encapsulated in nanoparticles constitutes an original approach to the prevention of neuropathic pain. In this study, we will identify miR-21 target genes that are regulated in macrophages and contribute to the induction of neuropathic pain. Then, based on the rationale that miR-21 targets may change in neuropathic pain maintenance, we will identify target genes in macrophages at 14 days after nerve injury. Finally, in a model of inflammatory arthritis we will identify miRs which are dysregulated in DRG neurons, affect the phenotype of macrophages, and contribute to the maintenance of pain. We propose that by comparing and contrasting neuropathic and arthritis pain models we will identify novel mechanisms operative within the DRG, and define specific pathways and mediators, which impact on the chronicity of pain. By combining microarray analyses with behavior and cell cultures in transgenic mice, macrophage functions and extracellular vesicles characterization, we will define the impact of neuron-derived miRs on macrophage function and phenotype in the DRG in neuropathic and inflammatory allodynia. Furthermore, we will establish whether manipulation of miRs and their target genes in macrophages provides therapeutic analgesia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Direct Transduction and Regulation of Pathological Pain by Neuronal TRPM2 Channels
Funder: Medical Research Council

Abstract: TRPM2 is expressed in immune cells (immune TRPM2) and sensory DRG neurons (neuronal TRPM2). Although immune TRPM2 is known to promote pain indirectly by facilitating immune-inflammatory responses, the function of neuronal TRPM2 is less understood. The objectives of this research are to define the role and mechanisms of neuronal TRPM2 in the direct transduction and regulation of acute and chronic pain. To determine the mechanisms of acute arthritis pain mediated by TRPM2, we will isolate DRG neurons from wild-type and TRPM2 knockout mice, and then monitor their acute activation and firing in response to nociceptive stimuli using calcium imaging combined with whole-cell patch clamping. Co-expression between TRPM2 and receptors for nociceptive stimuli in DRG neurons will be examined using immunohistochemistry in combination with in situ hybridization. To investigate the mechanisms of TRPM2 in chronic arthritis pain, we will generate antigen-induced arthritis (AIA) in mice in which HIF-1alpha in DRG neurons has either been genetically knocked down with siRNA or pharmacologically inhibited. We will then assess primary joint pain and secondary thermal and mechanical hyperalgesia followed by quantifying gene expression in DRG neurons with qRT-PCR. To identify other genes regulated by TRPM2, RNA-seq will be used to detect differentially expressed genes in DRG neurons between wild-type and TRPM2 knockout mice during AIA. To specify the role of neuronal TRPM2, we will selectively delete neuronal TRPM2 by breeding floxed TRPM2 mice with Advillin-Cre mice. We will then monitor pain behaviours after inducing acute and chronic arthritis pain in these mice. Meanwhile, joint inflammation will be assessed by measuring joint diameter and cytokines/chemokines together with analysis of joint histology. Altogether, this research will establish neuronal TRPM2 as a direct transducer and regulator of arthritis pain, and demonstrate therapeutic potential of TRPM2 inhibitors.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Brain region-specific immune responses driving concussion-related injury
Funder: Medical Research Council

Abstract: Concussion, or mild traumatic brain injury, affects millions world-wide each year. It is now appreciated that concussion increases the risk of developing long-term emotional and cognitive disorders such as anxiety and depression and neurodegenerative disease. Inflammation is a key regulator of brain injury and preliminary data show that two understudied brain regions, the meninges and cerebellum, may be more sensitive to inflammation and drive concussion-related symptoms. Aims and objectives 1) Define immune cell-mediated inflammation in the meninges and cerebellum in a mouse model of concussion 2) Investigate if communication between the meninges and cerebellum underlie emotional and neurological disorders in this model 3) Examine meningeal and cerebellar abnormalities in human concussion to provide biomarkers for treatment options Methodology We will use a well characterised a clinically relevant model of single and repeated closed-head injury in mice, to investigate the mechanisms of concussive injury. Flow Cytometry, immunofluorescence, Hyperion Imaging Mass Cytometry and RNA-sequencing will define the immune response in the meninges and distinct brain regions, including the cerebellum. Through various pharmacological and genetic cell-specific targeting techniques, we will remove defined immune cell populations from the brain and assess emotional and cognitive behaviours after concussion. Finally, we recruit patients with acute head injury or history of concussion and perform the latest MRI and PET-MRI protocols to assess meningeal and cerebellar abnormalities. Scientific/Medical opportunities New imaging protocols will establish diagnostic biomarkers for human concussion. The neuroimmunological mechanisms will be relevant across a broad range of injury and disease, where meningeal inflammation is present. This work will be the foundation of a research program that will include the investigation of concussion as risk for neurodegenerative disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Cells in limbo: mapping senescent cells and their associated inflammatory response in human brains with Alzheimer’s Disease
Funder: Medical Research Council

Abstract: Scientific abstract (around 400 words – max. 3,500 characters including spaces) Outline the overall aim and importance of the research, the specific research objectives, plan and methodology, including experimental design Address any clinical and translational research issues, specific goals/plans for medical/public health exploitation/applications, and refer to any IPR implications (see Guidance Notes). Cellular senescence is a stress response that prevents the expansion of old or damaged cells. Besides the irreversible cell growth arrest and resistance to apoptosis, one of the most intriguing features of senescent cells is their senescence-associated secretory phenotype or SASP, that accounts for most if not all the physiological and pathophysiological effects of senescence. The SASP includes pro-inflammatory cytokines and chemokines that strongly link senescence with inflammation. As we age, failure to eliminate senescent cells and its subsequent accumulation exacerbates the secretory phenotype contributing to chronic inflammation. Even though the accumulation of senescent cells is a key hallmark of ageing, and ageing the biggest risk factor for Alzheimer´s Disease (AD), the extent of senescence in the AD brain remains elusive. I hypothesize that senescence-induced inflammation in the brain contributes to the onset and/or progression of AD. Here, I propose to search for senescent cells in human post-mortem brains to systematically characterize the extent of senescence and the associated inflammatory response during AD, and identify which brain cell types are involved and when. With this aim in mind, we have established a collaboration with the UCL Brain Bank for the provision of human samples, and with Dundee University for the proteomic characterization of the senescent secretome. Understanding the mechanisms of cellular senescence may unveil new ways to balance neuroinflammation in order to delay or treat AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Characterisation of autoantigen-specific human B cells in central nervous system autoantibody-mediated diseases
Funder: Medical Research Council

Abstract: Autoantibody-mediated illnesses are rare throughout medicine. By contrast, over twenty currently exist in neurology. In these conditions, a focused characterisation of the autoantigen-specific B cell lineage offers a highly tractable opportunity to accurately study the underlying human pathology and simultaneously identify highly selective drug targets. As a paradigm, I will use CASPR2-antibody encephalitis as a model disease. My aims are to: 1. Track the maturation of CASPR2-specifc B-cell lineages across key human lymphoid compartments. I will identify the earliest CASPR2-reactive B cells and their development through lymph nodes into their key site of pathogenic autoantibody production: cerebrospinal fluid (CSF). This will exploit our established methods to isolate individual CASPR2 B cells. 2. Characterise the CASPR2-specific B cells in blood and CSF, to identify molecules which mediate their striking concentration in CSF. Flow cytometry and single cell transcriptomics will identify molecules exclusive to CASPR2-specific B cells. These may represent highly-selective future drug targets and mediate their observed preferential migration to or retention within CSF. 3. Compare the relative pathogenicity of CASPR2-specific monoclonal antibodies (mAbs) derived from CSF B cells in Aim 2. Well-established in vitro and in vivo models will explore the dominant mechanisms of CSF mAbs. This will identify the most pathogenic mAbs as disease biomarkers and their transcriptomes (derived from Aim 2) as even more specific future drug targets. Overall, these data will molecularly profile a well-defined 'pathway to pathogenicity'. Biologically, they will generalise to identify human autoreactivity checkpoints and mechanisms of B cell access to the CSF. Clinically, the proposal creates a precision medicine paradigm across autoantibody-mediated diseases which will translate to improved treatments for these and other established and putative neuroimmune conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Modelling the neuroimmune system
Funder: Medical Research Council

Abstract: This application is a UK-Canada exchange project relating to regenerative medicine. Regenerative medicine is defined as the branch of medicine that develops methods to regrow, repair or replace damaged or diseased cells, organs or tissues. The purpose of the project is to provide new skills to researchers, including ECRs, technicians and newly independent investigators, and to build links between UK and Canada based scientists for continued or future collaboration. The exchange will support the work being undertaken on the project "Modelling the neuroimmune system".


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Bi-directional communication between neurons, immune and stromal cells in rheumatoid arthritis
Funder: Wellcome Trust

Abstract: About 1:100 people in the UK live with rheumatoid arthritis (RA), an autoimmune disease that causes swollen and painful joints. We now have drugs that treat joint swelling effectively, but they are not great at reducing pain. As a result, pain is rated as one of the top concerns by individuals who suffer from RA. Scientists studying the disease are often divided into two camps: immunologists who study inflammation and neuroscientists who study pain. Our team aspires to bridge the gap between the two disciplines and improve pain research in RA. We will re-examine current literature to find out which cell types are most likely to sensitise nerves and cause pain in RA. We will study their interactions using human cells in a dish. Human nerves will be made from stem cells originating from people’s skin. Other cells which interact with them, such as immune and connective tissue cells, will be taken from the joints of RA patients.Together, our team hopes to identify how the many different cell types in the joint may talk to nerves and cause pain in RA. Our findings have the potential to speed up the development of better painkillers for this agonising disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: The potential role of IL-2 in preventing autoimmunity after alemtuzumab in multiple sclerosis
Funder: Wellcome Trust

Abstract: Multiple sclerosis (MS) is a common autoimmune disease of young adults, in which the patient’s own immune system attacks their brain and spinal cord, causing disability. Alemtuzumab is a highly effective treatment that depletes lymphocytes (cells that normally fight infection but some of which cause damage in MS). After treatment, the immune system returns without the MS-causing cells. However, in 40% of patients, as a consequence of treatment, the recovering immune system attacks another organ instead (e.g. the thyroid gland), limiting our use of alemtuzumab. This complication partly results from an imbalance between self-reactive lymphocytes, and regulatory cells, which specialise in controlling the self-reactive lymphocytes. Boosting regulatory cell numbers after alemtuzumab could therefore prevent autoimmunity. Interleukin-2 (IL-2) is a naturally occurring substance shown to increase regulatory cell numbers and suppress autoimmune disease. Using laboratory-based experiments, mouse studies and short dosing studies in patients, I will determine whether IL-2 can also increase regulatory cells after alemtuzumab treatment, hopefully providing evidence for a future clinical trial. Preventing post-treatment autoimmunity would represent an important advance in the management of MS, saving the NHS and patients considerable costs. The wider implication of my work is a general strategy for manipulating human immune reconstitution.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Exploring the Role of MITOchondrial ImmunoMETAbolism in Neuroinflammation: Mechanisms and New Targets for Progressive MS Treatment (MITO_META)
Funder: Wellcome Trust

Abstract: People with progressive multiple sclerosis (P-MS) have substantial unmet clinical needs. While current therapies for MS are focused on manipulating the activity of the adaptive immune system, they have limited applicability for P-MS where a switch towards the chronic activation of innate immune cells, such as mononuclear phagocytes (MPs), occurs. MITO_META aims to test the hypothesis that the detrimental activation of MPs in P-MS is dependent on their mitochondrial metabolism and that targeting mitochondrial complex I (CI) activity in MPs will lead to novel therapeutic approaches for P-MS. To achieve this aim, I will adopt a combination of animal models and post-mortem biological samples obtained from MS patients. I will initially use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to study the effect of removing Complex I from MPs during neuroinflammation (Aim 1). I will then analyse how the metabolism of MPs changes during neuroinflammation, and compare these findings to those obtained from post-mortem analysis of people with progressive MS (Aim 2). Elucidating the role of mitochondrial function in MPs during chronic neuroinflammation will advance our understanding of P-MS and lead to new therapies to interfere with the progression of disability.

Lay abstract: In multiple sclerosis (MS), the immune system attacks the central nervous system causing acute clinical symptoms, or relapses. Although there are therapies to stop relapses, most patients still develop a secondary progressive form of MS (P-MS) causing chronic disability, for which there is no cure. The damage in P-MS is caused by immune cells called mononuclear phagocytes (MPs). The aim of MITO_META is to reduce the harmful activation of MPs by targeting the way they produce energy (metabolism) in their powerhouse (mitochondria). I plan to use mouse models of MS (i) to abolish the harmful expression of a mitochondrial protein in MPs, and (ii) to investigate their changes in metabolism. I will then compare these findings to post-mortem data of people with progressive MS. This multi-step approach will lead to significant advances in our understanding of P-MS and allow us to develop new therapies to stop progression.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: How does aberrant innate immune activation damage the microvasculature of the brain?
Funder: Wellcome Trust

Abstract: Systemic lupus erythematosus and Aicardi-Goutières syndrome are chronic autoimmune disorders which can affect the brain of adults and children. Despite their high disease burden, there is no effective treatment for the neurological manifestations of these conditions, highlighting the need to identify defined immune pathways which drive brain damage. These diseases are characterised by aberrant activation of the type I interferon response and we have shown this pathway can damage small blood vessels of the brain. However the cellular and molecular mechanisms by which this occurs are unknown. In this proposal we will develop mouse models of interferon dysregulation, linked to human experimental medicine studies of "interferonopathic" diseases such as neurolupus. Our overarching aim is to understand the role of this pathophysiological axis in mediating brain disease in disorders such as lupus, with a view to developing therapeutic interventions. Goal 1. To determine the cellular and molecular targets of type I interferon within the brain’s microvasculature. Goal 2. To identify the influence of type I interferon subtype on microvascular disease Goal 3. To understand how microvascular disease arises in a lupus model of spontaneous interferon activation

Lay abstract: A healthy brain requires an excellent blood supply. This blood supply depends on a network of tiny vessels called capillaries, which are fragile and easily damaged. Damage to these small blood vessels can cause brain disease. Therefore finding out what damages these vessels could lead to an opportunity to prevent such diseases. We have shown that an immune molecule called interferon can damage the small blood vessels of the brain. This is a protein which the immune system produces to fight viruses, but sometimes the body produces high levels of interferon when the immune system malfunctions. We will identify how and why this damage to the small blood vessels occurs. In particular we will try to work out if we can prevent brain damage in immune diseases where interferon levels are high for many years, such as systemic lupus erythematosus, an immune disease which affects millions of people worldwide.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Molecular Targets Open for Regulation by the gut flora New Avenues for improved Diet to Optimize European health (TORNADO)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Europe is facing major diet related health problems Attitudes to eating habits have to be changed and the benefits of alternative treatment regimes substantiated. This can only be achieved by providing guidelines regulating health claims based on scientific data. Thus, there is a unique opportunity to use gut flora in potential treatment regimes and as a preventive target for major diet related health problems TORNADO consortium of which IFR is a partner, proposes a systemic and comprehensive mechanistic approach to deliver scientific data that can be compiled as guidelines for European authorities. TORNADO will determine the influence of diet on the gut flora and highlight the impact of gut flora on the immune system/other organ systems TORNADO aims to investigate molecular targets that are subject to regulation by gut flora and diet that sustain health. This will be done by an increasing level of specificity, from (1) investigations of dietary habits and health in population cohorts, through (2) intervention studies in humans and animals. TORNADO will deliver data that can be used to recommend biomarkers for evaluating effects of diet or microbes. TORNADO’s program will accelerate future design of personalized functional food for specific target groups.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL