NIHRDataInsights/HRCSData huggingface dataset:
Title: The cerebral signature of motor neuron disease: A combined MEG and MRI study across symptomatic phenotypes and pre-symptomatic gene carriers.
Funder: Wellcome Trust

Abstract: This project will combine a powerful MRI brain scanner with a technique called magnetoencephlography (MEG), which can non-invasively record brain activity in real time. If MND affects wide networks across the brain, we expect that alterations in neuronal rhythmic activity as an inevitable consequence; this is detectable with MEG. We will study MND patients soon after diagnosis and compare them to those with conditions that mimic MND. We will also contrast MND patients with fast versus slow rat es of progression to determine what underlies these differences and how we might develop ways to stop progression of symptoms Finally, this project will study changes in the brain that precede the onset of symptoms While for most patients there is no clear reason for developing the disease, a minority have multiple family members at risk due to mutations or expansions in the genetic code. This project will study people who are known to carry genetic abnormalities placing them at very high ris k of MND, in order to try and capture the very earliest signs of nerve damage. Such changes might reveal new targets for preventative drug therapy that then also have value in slowing progress in those with established disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying the pathogenic triggers of CD8 T-cells in multiple sclerosis .
Funder: Wellcome Trust

Abstract: Multiple sclerosis (MS) is the most common neurological disease affecting young adults and is widely considered to be an autoimmune disease i.e. whereby the body's immune system attacks itself - in the case of MS, the brain and spinal cord. we think that a particular type of white blood cell called T-cells are responsible for the damage caused in this disease. However, we still do not know how these T-cells become activated in the first place or specifically what they are attacking at a microsco pic level. In this project, I will analyze cerebrospinal fluid and blood samples from MS patients and determine what has triggered the disease. Using state-of-the-art techniques I will determine what is causing these cells to be active and how they are causing the disease symptoms It is hoped that understanding this could ultimately lead to new treatments for patients with this disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Metabolic reprogramming during neurogenesis: roles for the Notch pathway. .
Funder: Wellcome Trust

Abstract: Adequate production of energy is central to normal functioning of cells and organisms Although often assumed to be stable, metabolic pathways that control this energy production are actually subject to extensive regulation. This is exemplified by the diverse ways mitochondrial diseases can affect the nervous system, or by the changes in energy production that some cancer cells undergo during oncogenic transformation. Development of the visual lobes of a drosophila brain has been studied exten sively as a reductionist model of development of the mammalian brain, as well as for the initiation of tumorigenesis. In the course of this research project, I will assess whether the stem cells that generate these brain lobes produce their energy in a different way than their neuronal progeny. In addition, I will determine which genes are involved, and how they are regulated by the Notch pathway, which is implicated both in normal and pathological development in many tissues. Better understan ding of these events will advance our understanding of mitochondrial disorders, neurodegeneration and cancer in humans and potentially lead to novel therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Quality of Life following ALS (QoL-fALS) (Grant Extension)
Funder: Motor Neurone Disease Association

Abstract: To investigate quality of life in people with MND/ALS longitudinally. Benefits to MNDA and DeNDRON MND CSG if participants recruited to study appear in portfolio; aim is to recruit 500 people with MND. Underspend of grants Young/6026 and Young/6350 because: a) we found patients preferred us to interview them at home and the travel costs for the researcher to travel were cheaper than we had budgeted for patients and carers to travel; b) we did not recruit the administrator and instead the PI Prof Young organised the study, because we found that patients really wanted consistent consultant co-ordination throughout when we were consenting them for study entry, c) Leeds University has agreed to forego the statistics funding if the money can be rolled into the ongoing work.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Analysis of the role of amyloidogenic peptides in vascular inflammation and thrombotic complications of Alzheimer disease
Funder: Alzheimer's Research UK

Abstract: Although principally a disease of the brain, AD has also been associated with dysfunctions of the cardiovascular system. In particular, a growing amount of evidence shows that AD patients are at greater risk to develop vascular diseases of the brain such as stroke and that the dysfunction of the blood vessels associated with the brain plays a significant role in the development and progression of AD. To date most AD patients show deposition of amyloidogenic Aβ peptides in blood vessels, where they may cause vascular complications, including inflammation and thrombosis, which is the development of unwanted blood clots and vascular obstructions. Plasma Aβ peptides have been suggested to affect the function of platelets, which are small circulating cells responsible for blood clotting in healthy conditions and in disease (i.e. thrombosis). In this study we will investigate the ability of Aβ peptides to: 1) directly bind to platelets and promote platelet adhesion; 2) increase blood clot formation; 3) induce vascular cell inflammation; 4) enhance platelet/endothelial cell adhesion. The information provided by this project will allow better understanding of progression and complications of AD and, in the long term, will improve healthcare for AD patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;BLOOD
Title: Evaluating the Family Nurse Partnership Programme in England: a Randomised Controlled Trial
Funder: Department of Health (England)

Abstract: Background The Family Nurse Partnership (FNP) is a structured programme of home visits delivered by specially trained nurses for at-risk first time mothers. Part of the Child Health Promotion Programme, this intensive intervention has been introduced to address the elevated risk of social exclusion and health disadvantage that such women and their off-spring face. The programme aims to modify behavioural risk factors and enhance protective factors through regular home visits that start in early pregnancy and continue until the child’s second birthday. Based on the original US programme which has been widely evaluated, the FNP is currently undergoing formative evaluation at 10 English sites. Ten more sites will join to form a sample for a trial of the effectiveness and cost-effectiveness of the FNP. Aims Our study aims firstly to evaluate the effectiveness of the FNP within three outcome domains: pregnancy and birth, child health and development, and parental life course and self-sufficiency. One primary outcome has been specified in each domain: birth weight, emergency attendances / admissions within two years, proportion of women with second pregnancy within two years respectively. Secondary outcomes include health threatening behaviours, self efficacy, social support, child health and development, maternal life course. Our study will assess the incremental costs and consequences of the FNP compared to existing child services. Thirdly, our study aims to evaluate what processes vary the impact of the FNP, to assess its relevance to other settings and to optimise its future implementation. Plan of Investigation This individually randomised controlled trial with parallel process evaluation (qualitative and quantitative) and economic modelling studies will last 52 months. Following recruitment and baseline assessment via face-to-face interview, 2400 nulliparous women (ideally Potential Impact The UK government is extending the pilot FNP in England as part of universal child health services. However, whether the benefits found for the programme in the US will be replicated in England, which has more comprehensive child health services, is unclear. The formative evaluation of FNP has shown that women find it acceptable and that practitioners can implement it with fidelity but there remain bureaucratic difficulties which limit implementation. This trial will formally evaluate the FNP in England to provide the evidence base for subsequent policy and funding decisions. If no benefit is found, then government resources can be appropriately re-allocated, whilst if it is beneficial further opportunities for enhancement can be identified.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL;BLOOD
Title: POLYMER NANOMEDICINE: ENHANCING THE TRANSLATION FROM THE LAB TO THE CLINIC
Funder: Engineering and Physical Sciences Research Council

Abstract: There is a necessity to speed up the process of design, optimization and evaluation of formulation for biomedical applications. Such a process is even more crucial when it comes to the engineering novel nanometer-sized particles that can deliver therapeutic agents across the different barrier targeting only the damaged sites. Today such effort collectively known as Nanomedicine, is revolutionizing traditional therapy and enabling completely new therapeutic and diagnostic approaches. Nanomedicine is a multifaceted discipline that involves physicists, chemists, engineers, biologists and clinicians. This interdisciplinary nature is possibly nanomedicine greatest strength and greatest weakness at the same time. Indeed while this allows a more complete understanding of the different physico-chemical aspects as well as the biological implications, often the methodologies and the approaches are substantially different across the different disciplines hindering the validation and the fast translation of the final results. Herein we propose a rigorous approach of synthesis and pre-clincial evaluation of many nanoparticles for the delivery of theraupetic genetic materials. These will be screened developing and employing state-of-the-art biological evaluations adapted for nanoparticles. We plan to screen for thousands of formulation and aiming to identify few that will have a tremendous impact in both cancer therapy and motoneuron-degenerative disorders.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: BEM++ Stage 2
Funder: Engineering and Physical Sciences Research Council

Abstract: Many real-world problems in homogeneous media, such as electromagnetic scattering from an airplane or the noise radiation from a car, can be formulated as integral equations over the boundary of the domain. The advantage of such formulations is that only


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Development of a questionnaire to measure instrumental activities of daily living (I-ADL) in patients with primary brain tumors
Funder: Friends of EORTC

Abstract: Activities in daily living can be divided into two categories, basic activities of daily living (BADL) and instrumental activities of daily living (IADL). BADL include basic skills such as feeding, bathing and dressing. IADL on the other hand, include more complex activities such as food preparation, ability to handle finances, shopping or housekeeping. These capacities are required for autonomous functioning. Because IADL are higher order activities, they may therefore be negatively influenced by cognitive decline, which is characteristic of brain tumor patients. Therefore, especially limitations in I-ADL are informative of the brain tumor patient’s functioning in daily life. Currently, there is no questionnaire available to measure IADL in brain tumour patients. Therefore, the aim of this project is to develop a reliable and valid questionnaire to measure IADL in patients with brain tumors.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Structural analysis of Netrin 1 signal initiation and transduction
Funder: Medical Research Council

Abstract: We will study the molecular mechanisms of NET-1 signalling, a crucial pathway in cell and axon migration and cell-to-cell contacts. NET-1 signalling is important for human health with implications spanning from neurodegenerative diseases to cancer. We will study the molecular mechanisms of NET-1 signal initiation by NET-1 interactions with its receptors and signal transduction at the plasma membrane. We will use a combination of X-ray crystallography to obtain high-resolution molecular snapshots of extracellular NET-1 receptor complexes, biophysical methods to characterise interfaces and complex stoichiometries and live-cell fluorescence microscopy, using full-length NET-1 receptors, to relate our molecular analysis to the cellular and physiological context. Interrelated aims are: - To determine crystal structures of NET-1 complexes with the ectodomain constructs of NEO1, DCC and UNC5 receptors to obtain detailed molecular interface information, interaction stoichiometries as well as insights into the mechanisms of NET-1 signal modulation. - To biophysically characterise the NET-1-NEO1/DCC-UNC5 extracellular stoichiometry and interface properties using SPR, ITC, MALS and SAXS. Our structural data will allow us to design site-directed mutants that selectively impair the ability of NET-1 to interact with its receptors. - To validate the observed NET-1-NEO1/DCC binding mode within a cellular context, using full-length transmembrane NEO1/DCC receptors. We will employ FRET/FLIM in live COS7 cells to unravel signal transduction via the NET-1 receptors DCC, NEO1 and UNC5 and test the impact of structure-guided mutations in the observed interfaces. - To test the importance of the competition between NET-1 and two other protein families that bind NEO1 and DCC respectively, RGMs and CBLN4. We will employ competition binding assays to test the effect of NET-1 on RGM-NEO1 and CBLN-DCC binding and on NEO-1/DCC clustering in FRET/FLIM experiments in live COS7 cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Development of a refined model of neuropathic pain: a model without frank nerve injury
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Neuropathic pain occurs as a result of a lesion in the nervous system. It is a debilitating condition that due to the lack of effective treatments has become a major healthcare issue. Much of our understanding of the mechanisms of neuropathic pain has been gained through the use of nerve injury models. These are severe models that cause significant suffering for the animals. There is an urgent need for better models of neuropathic pain that reduce suffering with fewer adverse effects. In nerve injury models, cutting or ligating axons causes cessation of axonal transport. Axonal transport disruption leads to physiological changes that drive neuropathic pain mechanisms Work from our laboratory has shown that the local application of the anti-mitotic agent, vinblastine, causes the transient disruption of axonal transport along intact axons and the rapid development of mechanical allodynia (hypersensitivity to touch), a sign of neuropathic pain, that reverses by week two. These changes occur in the absence of axonal degeneration with no obvious adverse effects to the animals. Our data suggests that the local application of low doses of anti-mitotic agents to the rat sciatic nerve provides a way of mimicking nerve injury. This studentship will extend our initial studies and investigate whether the local application of mitotic agents can replace existing nerve injury models as a refined model of neuropathic pain without the adverse effects. It will also determine whether a non-surgical method for induction is possible. It will specifically examine the effects of the chemotherapy agents vinblastine and paclitaxel on pain behaviours and neuronal physiology and compare these findings to the literature on nerve injury models. Since both agents can cause chemotherapy-induced peripheral neuropathy (CIPN) we anticipate that this model will also provide a novel model for investigating CIPN with a view to future prevention of this very disabling complication of chemotherapy.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Magnetic Resonance Imaging to Characterise Invasive Phenotypes in Cerebral Gliomas
Funder: Department of Health (England)

Abstract: High grade gliomas are aggressive tumours that are usually rapidly fatal despite intensive treatment. If we could identify patients with limited spread, they might be suitable for aggressive local therapy. New imaging techniques allow non-invasive study of tumour pathology. Diffusion tensor imaging (DTI) identifies occult tumour invasion with a sensitivity of 98% and specificity of 81%, and can predict patterns of recurrence. Further information can be obtained on angiogenesis (Dynamic contrast enhanced Mr. – DCE) and metabolism Mr. spectroscopy (Mr.S).Specific aims of the research:1. Use Mr.I markers to predict invasive behaviour of gliomas to differentiate limited invasion from diffuse invasion.2. To correlate Mr.I markers with biological features of invasiveness:Outline plan of research:1. Identification of Invasive Phenotypes using Mr.I: multimodal Mr.I will be performed on 145 pre-operative patients with high grade gliomas. Measures of DTI, DCE and Mr.S will be correlated with patterns of recurrence on follow up imaging.2. MALTING Trial multimodal Mr.I will be performed on 95 patients undergoing glioblastoma resection. All patients will be treated with 5ALA-guided resection and Gliadel with post-operative. Primary outcome is the percentage of patients alive at 2 years. Outcome will be compared to predictions from published normograms3. Imaging correlation with biological markers of invasiveness: this will correlate the imaging-based markers of invasiveness in 50 patients with:a. Concentration of extracellular growth factors and cytokines (esp. metalloproteinases and their inhibitors) measured by microdialysis;b. Cellular measures of invasion from expression of MT1-MMP and in vitro measures of invasion.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Modelling non-compliance in randomised controlled trials with survival outcomes
Funder: Department of Health (England)

Abstract: Objective: Develop and apply methods to adjust for time-dependent patient non-compliance when estimating treatment efficacy in the analysis of randomised controlled trials with survival outcomesDesign: Statistical modelling and simulation techniques to develop and validate methodology, using empirical data sets from cancer and epilepsy trials to apply and test methodsExpected outcomes: User-friendly method of statistical analysis adjusting for non-compliance in survival analysis; dissemination of methods to maximise usageBenefits to health care: Information about effect of compliance on expected treatment efficacy, thus allowing patients to appreciate the importance of, and to make informed decisions regarding, compliance with treatment protocol


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Improving the experience of out-patient cancer treatment for people with comorbid dementia in Wales
Funder: Tenovus Cancer Care

Abstract: Cancer specialists are treating a growing population of older people who are suffering with both cancer and dementia. Memory loss and an inability to understand and retain new information are problems that affect those with both dementia and milder cognitive impairment. For the cancer patient who also has dementia such problems can influence decisions concerning their cancer treatments (including side effects) and symptom management. To date there has been little research to investigate such issues. We propose to conduct a study at Velindre cancer centre (VCC): an in-depth examination of the experiences of people receiving out-patient treatment who have cancer and comorbid dementia and their families. We will estimate the number of patients with diagnosed dementia, observe clinical practice across a selection of out-patients clinics (n=4) and conduct interviews with patients and families. The study will investigate the potential to improve the experience of cancer and dementia patients and their families. We anticipate improvement in supportive care could not only benefit their quality of life, but also result in better management of symptoms and cancer treatment side-effects, thereby reducing service costs. In addition, the project will create an opportunity for the staff at VCC to establish a collaboration with the School of Healthcare Sciences, Cardiff University enabling the next stage of this research programme to develop and test a new supportive clinical intervention for cancer and dementia patients and their families.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS
Title: Oxidative stress as a causal mechanism for chemotherapy-induced pain.
Funder: Wellcome Trust

Abstract: Neurotoxicity is the major dose-limiting side-effect of chemotherapy causing pain in hands/feet, resulting in otherwise effective (i.e. anti-tumour) chemotherapy being stopped. There is no treatment for chemotherapy-induced pain and little knowledge of its mechanisms We hypothesize that chemotherapy-induced pain is caused by reactive oxygen species (ROS) generation in sensory nerves. Transient receptor potential A1 (TRPA1) channels in nerves respond to ROS and are linked to pain perception. Thu s we further hypothesise that chemotherapy-induced ROS evokes pain via TRPA1. Using translational models of chemotherapy-induced pain, which mimic the scenario observed in patients i.e. multiple treatment cycles evoking pain, our key goals are: 1) Evaluate the therapeutic potential of inhibiting ROS. ROS scavengers will be administered to test if chemotherapy-induced pain can be reversed or prevented. 2) Establish if ROS levels are increased in sensory nerves, and in which type of neurones /cells. ROS expression will be correlated to the timecourse of chemotherapy-induced pain, identifying the neuronal/cellular target(s) and required timing of ROS inhibition to achieve greatest therapeutic benefit. 3) Investigate if chemotherapy-induced ROS evokes pain via TRPA1. TRPA1 antagonists/knockout mice will assess if TRPA1 blockade affects the development of chemotherapy-induced pain. Fluorescence imaging will identify if chemotherapy-induced ROS signal via TRPA1 channels.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;CANCER AND NEOPLASMS