NIHRDataInsights/HRCSData huggingface dataset:
Title: Does the exercise-regulated myokine β-aminoisobutyric acid protect against skeletal muscle dysfunction in diabetes?
Funder: Diabetes UK

Abstract: Type 2 diabetes mellitus (T2DM) induces loss of skeletal muscle function, quality, and mass which contributes to exercise intolerance, disability and decreased independence. Diabetic muscle dysfunction includes decreased mitochondrial function, capillary density, and impaired protein homeostasis, alongside pathological muscle remodelling. There are no treatments for this neglected diabetic complication. Exercise reduces T2DM-induced muscle dysfunction. The metabolite β-aminoisobutyric acid (BAIBA) is secreted from muscle during exercise. BAIBA activates exercise-like muscle remodelling, improving muscle force, fatigue resistance and mitochondrial function. We will investigate whether BAIBA reduces diabetic muscle dysfunction. Human primary myocytes from healthy donors and people with T2DM will be treated with BAIBA. Mitochondrial respiration, protein anabolic and catabolic pathways, structural remodelling, and glucose and fatty acid metabolism will be assessed in the myocytes. In mice, T2DM will be induced using a high-fat diet. Mice will be treated with BAIBA. We will use muscle force-fatigue assays to determine whether BAIBA reverses diabetes-induced muscle dysfunction. High-resolution respirometry will determine whether BAIBA improves diabetes-related muscle mitochondrial dysfunction. Light sheet microscopy will assess whether BAIBA counters diabetes-induced muscle vascular remodelling. Calorimetric wheel-running and treadmill assays will determine whether BAIBA reverses diabetic exercise intolerance. BAIBA may offer a critical therapeutic approach for diabetic muscle dysfunction.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;MUSCULOSKELETAL
Title: Metabolic Signalling
Funder: Medical Research Council

Abstract: Obesity is one of the greatest public health challenges of the 21st century. In the UK currently over 60% of the adult population is overweight with 1 in 4 adults being obese (BMI >30). Obesity is a major risk factor for a range of common morbid conditions including type 2 diabetes, cardiovascular disease, and cancer as well as having significant psychological and social impact. Body weight is regulated by a complex physiological system that controls food intake, nutrient storage and energy expenditure. The central nervous system plays a pivotal role in this regulatory mechanism. The hypothalamus and caudal brainstem have been implicated in the homeostatic regulation of body weight responding to a number of hormonal and neural systems that inform the brain about nutrient status. More recently it has become clear that other brain regions including the cerebral cortex, basal ganglia and limbic system potentially play roles in the regulation of metabolism. Recent genome wide association studies in humans have also strongly implicated neuronal genes as risk alleles for obesity. The overall aim of future work will be to further understand the CNS regulation of energy homeostasis. We will analyse the role of the hypothalamic signalling mechanisms we have implicated in the regulation of food intake and body weight extending studies to new brain regions and neuronal circuits. The work is divided into 4 programmes: Analysis of signalling pathways downstream of IRS proteins in the hypothalamic regulation of energy homeostasis. Analysis of AMPK cascade signalling components in the hypothalamic regulation of energy homeostasis. Studies on the midbrain dopaminergic system in the regulation of energy homeostasis and reward. Analysis of the function of defined neuronal circuits in the regulation of feeding behaviour using optogenetics. The first programme will identify signals downstream of Irs2 that regulate feeding and body weight. We have previously shown that deletion of Irs2 in the brain causes marked obesity. The second programme builds on our published and unpublished work demonstrating a key role for the AMPK cascade in the hypothalamus. The third programme will explore the role of non-homeostatic dopaminergic circuits that are thought be regulate the rewarding aspects of food. The final programme will start to exploit available technologies using light-modulated conductances that increase or suppress neuronal firing, to explore the function of appetite circuits in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: Characterising the mechanisms through which the HPA axis maintains homeostasis in health and disease: A multiscale, multidisciplinary approach
Funder: Medical Research Council

Abstract: This Programme Grant will integrate data obtained from cellular, tissue, whole animal, computational and mathematical models to investigate the biological mechanisms underlying the rhythmic activity of the stress-responsive hypothalamo-pituitary-adrenal (HPA)-axis. The purpose of the Programme is to test the hypothesis that dynamic oscillatory patterns of activity are intrinsic to the HPA axis and are crucial for the stability and reactivity of this critical homeostatic and stress response system. We shall determine how the HPA axis utilises dynamic oscillatory activity - across multiple spatial and temporal domains - to maintain homeostasis and how these activities respond to stress and disease. To address these questions we shall combine our mathematical modelling and in vitro and in vivo expertises, using a variety of techniques including molecular and chromatin biology, cell signalling, systems biology, computational neuroscience and applied nonlinear mathematics. We shall develop novel model-driven hypotheses through a predictive modelling framework - by which we mean an overarching framework that is informed by, and in turns informs, our experimental design. This framework will underpin the construction of a novel hybrid system (where the interaction between computer model and in vivo or in vitro experiment occurs in real time), which will permit experimental design in closer agreement with the natural system as well as reducing the number of animals required for experimental studies. Ultimately our aim is to understand the fundamental mechanisms of CORT rhythmicity so that glucocorticoid therapies can be reevaluated to maximize the therapeutic benefit, whilst minimizing side effects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: The molecular, cellular and circuit changes involved in the metabolic-olfactory feedback loop
Funder: Medical Research Council

Abstract: A feedback loop exists between the digestive and olfactory systems; metabolic state regulates olfactory sensitivity, while depressed olfactory sensitivity decreases food intake and improves metabolic health. How metabolic state alters odour processing and how this is linked to altered perception and feeding behaviour is poorly understood. This project focuses on the first stage of olfactory processing in the olfactory bulb. We will observe how metabolic state alters the transmission of odour information as it passes through the circuitry of the olfactory bulb. This will be achieved using dual-colour multi-photon imaging of the olfactory sensory afferents synapsing in glomeruli, together with the activity of periglomerular interneurons or mitral/tufted output neurons. Then the molecular, cellular and circuit level changes occurring in the olfactory bulb in response to altered metabolic state will be investigated using a multi-pronged approach employing: 2-photon imaging, electrophysiology, pharmacology, physiological manipulations as well as genetic knockdown. These experiments will reveal the molecular mechanisms that transduce metabolic signals and how they regulate this circuit. We will then link these circuit changes to perception and altered feeding behaviour by selectively disrupting this metabolic-modulation in defined cell types. The overarching aim of this project is to induce changes in the function of a neural circuit and link these changes to altered perception and behaviour. This approach will give insight into how the brain operates in general, but more specifically it will begin to detail how metabolic state modulates olfaction and what aspect of this modulation is responsible for regulating energy balance. Such knowledge may provide new pathways that could be targeted for the treatment and/or prevention of obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: Regulation of glucose homeostasis by brainstem astrocytes
Funder: Diabetes UK

Abstract: The brain orchestrates homeostatic responses to deviations from the normal glycaemic range by coordination with peripheral tissues. Although most published work in this area focuses on the hypothalamus, evidence exists for involvement of the brainstem dorsal vagal complex (DVC). The DVC is connected to the hypothalamus via direct neuronal projections. In turn, the DVC is bi-directionally connected, by the vagus nerve, to the pancreas, liver and gut. Astrocytes are an abundant glial cell type in the brain increasingly being recognised for their role in regulating physiology and behaviour. Utilizing Designer receptors exclusively activated by designer drugs [DREADD]-technology to specifically control DVC astrocyte activity, our preliminary data support a role for these cells in integrating and responding to changes in energy availability: DREADD-mediated activation of DVC astrocytes potently inhibits food intake in mice even when their drive to feed is enhanced by fasting. We hypothesize that DVC astrocytes are also involved in mediating the physiological response to deviation from glucose homeostasis by modulating vagus nerve output. This will be tested using DREADD-technology to interrogate how DVC astrocytes and vagal premotor neurons are involved in physiological responses to deviations from euglycaemia in lean mice and an obese mouse model of type-2 diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: (Neuro)Immune Regulation of Endocrine Organ Function
Funder: Wellcome Trust

Abstract: Building on the identification of macrophages which modulate sympathetic nerve signalling in adipose tissue (AT), our lab has recently also discovered tissue-resident macrophages within other endocrine organs thought to be sympathetically-innervated – including the adrenal glands (AGs). A role has not yet been described for these AG-resident macrophages, which localise to regions of both the adrenal cortex and medulla. Interestingly, a ring of macrophages unique to the female mouse inner-cortex suggests possible sexually-dimorphic immuno-endocrine interactions. Using bulk RNA-sequencing, whole-mount imaging and in vitro assays, I aim to phenotypically and functionally characterise male and female adrenal macrophages. I will compare the transcriptomes of male and female macrophages sorted from either the cortex or medulla, and use differentially-expressed genes between the sexes to find novel markers of female inner-cortical macrophages – which may also allude to their function. In addition I will also confirm the presence or absence of AG sympathetic innervation, as a role for these macrophages in the modulation of adrenal sympathetic nerve signalling similar to AT cannot yet be excluded. This will provide new insights into sexual dimorphism of immuno-adrenal homeostasis, which may underlie the incompletely understood pathologies of sex-biased adrenopathies such as polycystic ovary syndrome or Addison’s disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: How does insulin resistance increase risk of Alzheimer's disease?
Funder: Diabetes UK

Abstract: People with Type 2 diabetes (T2DM) have a two-fold increased risk of developing Alzheimer’s disease (AD). This transcends impact of age or cardiovascular complication, posing a serious clinical challenge. To counter this, it is vital to understand and target the molecular mechanisms that link T2DM and AD. We hypothesize that risk arises because insulin resistance in T2DM encourages hyperphosphorylation and aggregation of Tau, a pathological signature of AD. Dysregulation of insulin signalling in T2DM rodent and cellular models causes Tau hyperphosphorylation and impairs autophagic clearance of pathological Tau. Our unbiased genetic screen in an established Drosophila tauopathy model, identified a component of insulin signalling pathway that potently suppressed Tau-mediated degeneration. This causally links insulin resistance to pathological Tau. Our over-arching aim is to understand the mechanism underpinning this link. We aim to genetically unpick the complex pathways connecting these diseases, and investigate how insulin resistance causes abnormal Tau phosphorylation and impairs autophagic clearance. The impact of insulin-sensitizing /autophagy-activating drugs on Tau phenotypes will be assessed and our results will be validated in post-mortem human brain samples.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: Disorders of Thyroid Hormone Action: Diagnosis, Pathophysiology and Therapy
Funder: Wellcome Trust

Abstract: Having discovered that cystic degeneration of aortic media in human selenoprotein deficiency causes its aneurysmal dilatation, we will elucidate its pathogenesis using mice with conditional, aortic selenoprotein depletion and patients stem cell-derived vascular smooth muscle cells and determine whether antioxidants can inhibit this process. We will investigate structure-function relationships in SECISBP2, including how deficiency of this master regulator is variably rate-limiting for synthesis of different selenoproteins. Following our first identification of RTHalpha, a disorder due to TRalpha mutations with tissue-selective hypothyroidism but near-normal thyroid hormone levels, we will determine its genetic architecture and phenotypic spectrum. We will identify abnormalities in circulating metabolites and proteins to enable diagnosis of RTHalpha and guide its therapy. Aided by structural insights, we will design and test thyroid hormone analogues that disrupt mutant TRalpha-corepressor interaction, the basis of dominant negative inhibition which mediates pathogenesis of the disorder. We will develop biochemical markers to differentially diagnose RTHbeta cases from patients with TSH-secreting tumours and to guide RTHbeta therapy. In patients with deficiency of the MCT8 thyroid hormone transporter, we will trial whether treatment with triiodothyroacetic acid, a thyroid hormone analogue whose cellular transport is MCT8-independent, alters neurodevelopmental outcome.

Lay abstract: We study disorders with defects in genes controlling entry of thyroid hormones into cells, their conversion to the active hormone (T3) and action via two types of receptor, to better understand these processes. Defects in SECISBP2, causing deficiency of selenium-containing proteins, cause a multisystem disease with features including impaired thyroid hormone conversion and degeneration of the aorta. We will understand how aortic degeneration occurs using selenoprotein-deficient aortic cells from mice and patients and test whether antioxidants can prevent this process. Defects in thyroid receptor alpha, cause a disorder with features of thyroid underactivity although blood thyroid hormone levels are near normal. Gaining knowledge of its genetic basis, features and developing a specific diagnostic test will enable us to identify such patients who may benefit from thyroid hormone treatment. Defective hormone entry causes failure of brain development and we will trial whether treatment with a thyroid hormone-like drug can prevent this.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL
Title: The Role of Plant Cell Walls in Regulating Starch and Lipid Bioaccessibility from Plant Foods: In Silico In Vitro and In Vivo Studies
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The release ('bioaccessibility') of starch and lipid from plant foods in the gut plays an important role in influencing starch and lipid digestion, postprandial metabolism and gut hormone signalling. However, the mechanisms of nutrient release from plant food matrices are largely unexplored. Moreover, there have been no fundamental studies on the role of plant cell walls (PCW) in influencing nutrient release. The aim of this project is to understand how PCW ('dietary fibre') of exemplar foods (almonds and wheat) influence the bioaccessibility and digestion of intra-cellular starch and lipid and consequential effects on postprandial metabolism in humans. A multidisciplinary approach will be used, involving a novel combination of in silico, in vitro and in vivo methods to study starch and lipid bioaccessibility, digestion kinetics and postprandial metabolism. A mathematical model will be developed for predicting nutrient release from plant tissues using geometric theory and empirical data from microstructural analysis of plant materials and digestion studies. Model gut simulations of digestion will be used to study the effects of processing, mastication and gut environment on starch and lipid release and the role of PLW. Kinetic experiments on separated plant cells will be conducted to determine if amylase and lipase penetrates PCW and hydrolyses intra-cellular starch and lipid, respectively. In human studies, the effects of chewing and digestion on lipid release will be determined. Effluent from ileostomists will be used to quantify starch and lipid loss at the terminal ileum and examine 'digested' plant tissue microstructure. In human metabolic studies, we will also determine the effects of lipid and starch release on postprandial glycaemia, insulinaemia, lipaemia, and gut peptides GIP, GLP-1 and CCK. These studies will provide basic information to support the design of foods with starch and lipid absorption profiles beneficial to cardiovascular ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Defining a gut-brain-liver axis
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The brain controls hepatic glucose production through insulin-dependent and -independent pathways, including a gut-brain-liver axis which is activated following meals. Functioning of this axis is lost with high-fat feeding, contributing to the development of hyperglycaemia and type-2 diabetes (T2D). Interestingly, bariatric surgery can rapidly reverse diabetes, long before any effect on weight loss, and this has been attributed to alterations in gut-brain-liver signalling. Thus, bariatric surgery could be a cost-effective way to treat diabetes, even in non-life-threatening situations. The neuronal elements constituting the axis are unknown. A full understanding will elucidate mechanisms behind T2D and how its reversal by surgery. Furthermore, knowledge of intervention points may avoid a need for surgery. Using our expertise in gut-brain signalling, new transgenic mouse models and the latest virus technology, we will define the different components of the axis. We will measure how activation of brainstem neurones, identified as responding to meal-related stimuli, affects hepatic glucose production (which is uncontrolled in diabetes). This will be achieved by transfecting specific neurones with designer receptors, which can then be activated selectively with a designer drug whilst carrying out pancreatic insulin clamps. Then, utilising the latest viruses for anterograde tracing we will follow the route from the gut via the brainstem. We will investigate short-loop circuits within the dorsal vagal complex, but also longer loops which integrate neurones in the hypothalamus, culminating in autonomic regulation of the liver. Functionally distinct sub-populations will be characterised by their efferent connections and how they respond to endocrine and nutrient signals, through retrograde tracing and patch-clamp electrophysiology. Finally, we will identify synergy between central insulin signalling and independent neuronal pathways that together control glycaemia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Living with obesity surgery: The patient's perspective of important outcomes and follow-up care.
Funder: Department of Health (England)

Abstract: Obesity is an increasing health problem worldwide. Surgical treatment can lead to dramatic weight loss and improvement of weight-related illnesses, but also has associated risks. Current standard evaluation focuses on surgical complications that are important to clinicians, however, little is known about how surgery affects outcomes that are important to patients. This project will use existing literature supplemented by patient interviews and questionnaires to establish outcomes that patients consider to be important after obesity surgery and how post-operative support can be improved. This will will help researchers ensure outcomes important to patients are measured and help improve NHS services for obesity surgery based on patient needs.


Research activity codes: 6.4 SURGERY;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL
Title: Developing multi-scale models of digestion to enable targeted product solutions for nutrition and metabolic health
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our aim is to develop multiscale models of early digestion of food to enable targeted product solutions for nutrition and metabolic health. Upon selection of materials to study, our approach is summarised below: a) We shall study the biochemical digestion of food materials in the gastric and duodenal phase by subjecting these materials to the INFOGEST protocol. We will collect samples of the digestive fluid at regular intervals and store them for subsequent determination of nutrient release kinetics. In order to combine the physical and biochemical aspects of digestion, an in vitro gastric digestion will be set up and the digestive output will be used immediately as a starting material for an existing Peristaltic Duodenal Model which mimics peristalsis as it occurs in the small intestine. b) The rheology of the digesta will be measured as a function of residence time. The mechanical loads quantified from the Duodenal Peristaltic experiments described in part a) above will be used as boundary conditions to simulate damage and breakdown in computer simulations. The level of deformation and breakdown will be correlated with the nutrient release profile determined biochemically described above. The particle breakdown will also feed into the starting conditions for the simulations described in part c) below. c) An in silico mesoscale simulation that follows how macromolecules/bacteria move in highly complex fluids such as dense polymer solutions will be used to examine how molecules move across the mucus layer to reach signalling receptors and compared to results for the organoid experiments described below in part d). d) We will use our developed intestinal systems (human small intestinal gut organoids) to understand the interplay between metabolites and gut hormone release. The results will be used to validate the simulations described in part c) above.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL