NIHRDataInsights/HRCSData huggingface dataset:
Award Title: The emergence of GABAergic microcircuits in the cortex
Funder: Wellcome Trust

Abstract: The wiring of neurons in the brain is a highly dynamic process, where the number and strength of synapses between neurons are in constant flux. This period of brain development neatly encapsulates a central unanswered question in the field: how do circuits remain stable in the face of unrelenting change? This is further complicated by the fact that neurons process information at multiple spatial scales, from the local integration of synaptic inputs along individual dendrites, to the summation of dendritic events at the soma and the emergence of coherent activity in local microcircuits. Therefore, mechanisms that modulate activity across these different spatial domains must be present to control the flow of information in the brain. Here, we will focus on the emergence of GABAergic microcircuits by cortical interneurons, which modulate the ongoing activity of circuits in the brain. We aim to (1) trace the emergence of these circuits during development; (2) uncover the activity rules that controls their wiring and (3) establish the functional role they play keeping cortical circuits stable. Our findings will not only provide a unique description of circuit formation and plasticity, but also shed light on the homeostatic mechanisms employed by the brain to attain stability.

Lay Abstract: The brain is made up of millions of neurons that form trillions of connections with each other, allowing information to be passed across them. A fundamental question in neuroscience is to understand how these connections are formed, as neurons wire up during development. Neurons in the brain can be broadly divided into excitatory and inhibitory, depending on whether they stimulate or dampen brain activity. It is thought that a tight balance exists between the two, so that the brain is able to process information in a stable manner. Indeed, disruption of this balance has been implicated in many neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. We propose to explore the principles behind the wiring of inhibitory neurons in the brain. In so doing we aim to discover how circuits of connected neurons emerge during development and uncover the mechanisms by which they remain stable over time.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: NEUROLOGICAL
Award Title: The eye and brain: Evaluation of the retinal nerve fibres and vessels as markers of small vessel disease progression or regression on neuroimaging.
Funder: Stroke Association

Abstract: We aim to better understand the pathophysiology of small vessel disease (SVD), a cause of stroke and dementia, through use of multi-modal retinal imaging. Research indicates that brain MRI features of SVD not only progress but can also regress, so some of the brain damage may be reversible. However, MRI is not able to demonstrate the tiny brain blood vessels and nerves in detail. The retinal small vessels and nerves are developmentally related to those in the brain and can be seen in fine detail with high definition retinal cameras. 

We will use multi-modal retinal imaging, including optical coherence tomography (OCT) and OCT angiography, to augment detailed assessments of patients presenting with mild stroke as part of a funded study due to commence in 2018. Patients will undergo brain MRI including blood-brain barrier permeability imaging, cerebrovascular reactivity and diffusion imaging together with clinical assessments, cognitive testing, blood measurements and other tests.

Associations between retinal and brain imaging features and other study data will be investigated, at baseline and intensive follow-up over the first year after stroke, and annually thereafter for 4 years. Edinburgh is uniquely placed to conduct this work, having the imaging technology and cross-disciplinary experts in one place.

Lay Abstract: We aim to better understand the pathophysiology of small vessel disease (SVD), a cause of stroke and dementia, through use of multi-modal retinal imaging. Research indicates that brain MRI features of SVD not only progress but can also regress, so some of the brain damage may be reversible. However, MRI is not able to demonstrate the tiny brain blood vessels and nerves in detail. The retinal small vessels and nerves are developmentally related to those in the brain and can be seen in fine detail with high definition retinal cameras. 

We will use multi-modal retinal imaging, including optical coherence tomography (OCT) and OCT angiography, to augment detailed assessments of patients presenting with mild stroke as part of a funded study due to commence in 2018. Patients will undergo brain MRI including blood-brain barrier permeability imaging, cerebrovascular reactivity and diffusion imaging together with clinical assessments, cognitive testing, blood measurements and other tests.

Associations between retinal and brain imaging features and other study data will be investigated, at baseline and intensive follow-up over the first year after stroke, and annually thereafter for 4 years. Edinburgh is uniquely placed to conduct this work, having the imaging technology and cross-disciplinary experts in one place.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: NEUROLOGICAL;EYE
Award Title: The immunological basis of susceptibility to nontyphoidal Salmonella bacteraemia among HIV-infected adults in Uganda
Funder: Medical Research Council

Abstract: Nontyphoidal Salmonellae (NTS) cause fatal bacteraemia among HIV-infected Africans. Surprisingly, susceptibility initially increases on antiretroviral therapy (ART) and, although subsequently diminishes, it remains over 50-fold higher than in HIV-uninfected Africans. Candidate vaccines aim to induce antibodies against Salmonella lipopolysaccharide (LPS) O-antigen. Previously, I found that these antibodies occur in excess in some HIV-infected Africans and block killing of NTS, raising safety concerns. Blocking antibodies may represent one of a number of factors contributing to susceptibility. I propose an integrated hypothesis that NTS bacteraemia in HIV-infected Africans occurs due to: 1. high levels of NTS in the gastrointestinal (GI) tract,  2. translocation of NTS to the circulation secondary to loss of CD4+ Th17 cells and mucosal-associated invariant T (MAIT) cells,  3. dysregulated production of anti-O-antigen antibodies, secondary to translocated LPS and Tfh cell dysregulation; these antibodies are unable to kill translocated bacteria, resulting in bacteraemia. The experimental approach exploits the changes in susceptibility to NTS with ART and investigates blood, GI mucosa collected by endoscopy, and stool in a cohort of treatment-naïve HIV-infected adults in Uganda, immediately before and for 24 months after initiating ART, in comparison with HIV-uninfected adults. I will examine Salmonella in the GI tract by metagenomics, and its translocation to the circulation by 16S qPCR, and immunological and biochemical markers. Concentration and function of blocking antibodies will be determined by ELISA and bactericidal assays, while frequency and function of T cell subsets, focusing on CD4+ Th17 and Tfh, and MAIT cells, will be explored by flow cytometry. I will test for association between these parameters and findings will be correlated with time on ART. The detailed knowledge obtained will help guide the development of appropriate vaccines and therapies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: The impact of type 2 immunity on haematopoiesis and consequences for host immune function
Funder: Medical Research Council

Abstract: Haematopoietic stem cells (HSCs) sense peripheral inflammation allowing bone marrow immune cell production to adapt to ongoing demands. This is well understood for bacterial and viral infection with key roles for pro-inflammatory cytokines (e.g. type I/II interferons). In contrast, how HSC respond to type 2 inflammation represents a substantial knowledge gap. This is important as type 2 immunity is key for responses to helminth parasites and in allergic disease. Our preliminary studies show chronic infection with Schistosoma mansoni drives a type 2 bone marrow cytokine environment with substantial changes to immune cell progenitors (BM monocytes, LSK cells, HSCs). This is associated with weaker responses to re-infection maintained even after parasite clearance. We propose type 2 inflammation causes sustained alterations to HSCs with wide-ranging implications for both anti-parasite immunity and bystander immune responses to unrelated challenges.  We will first characterise how schistosome-induced type 2 inflammation impacts on mouse HSCs using single cell gene expression profiling (10x Chromium) and functional assays. We will assess the persistence of epigenetic changes (ATAC-seq) following parasite clearance. We will also determine if these gene expression signatures are present in schistosome-infected people. Next, we will identify the cytokine signals that drive these changes and test how HSC integrate type 2 (IL-4) and type 1 (IFN-I/g) inflammatory signals. Finally, we will assess the extent to which HSC training by type 2 inflammation underpins parasite immune modulation. We will determine whether infection-induced changes to HSC directly drive weak immune responses in chronic schistosomiasis. Finally, we will test how HSC integrate type 1 and type 2 signals and the consequences of this for trained immunity. To do this, we will test if parasite-induced changes to HSC lead to weaker responses to live vaccines (BCG) in both humans and in mouse models.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: The interaction of polygenic and monogenic diabetes to unravel new biology and diabetes subtypes
Funder: Wellcome Trust

Abstract: We are now in the genomics era where clinical and pre-emptive genetic testing is common. This has raised new problems in monogenic disorders such as Maturity-Onset Diabetes of the Young (MODY), a rare genetic form of diabetes: 1) identification of wide variation in the clinical features of people with MODY mutations, including non-diabetic individuals. 2) identification of people who are ‘MODY-like’ (slim, young and not on insulin) but without a MODY mutation and therefore without a known cause for their diabetes.
 
During my fellowship, I will address these new problems using our unique cohort of MODY/MODY-like diabetes and clinical and genetic data on 500,000 people from UK Biobank. I hypothesise that polygenic risk of diabetes-related traits will explain variation in the MODY phenotype and characterise new subtype(s) of diabetes which presents as classic MODY, but is due to extreme polygenic risk of diabetes-related traits (polygenic-phenocopies).
 
The outcomes of this research will be to provide accurate prediction of which people with MODY mutations will get diabetes and when, and define and characterise a new type of diabetes. This work will have important implications for individuals with MODY, for the wider diabetes community and will provide framework for other genetic disorders.

Lay Abstract: Maturity-Onset Diabetes of the Young (MODY) is a rare genetic form of diabetes. Identifying MODY is important for the correct treatment. We are now doing more genetic testing than ever before. This has led to two new problems: 1) We are now finding people with defective MODY genes but without diabetes and 2) we are finding people who are ‘MODY-like’ but without defective MODY genes. During this fellowship, I will aim to study these two problems in detail.
I will develop ways to accurately predict if and when people with defective MODY genes will get diabetes. I will also aim to identify a reason for this MODY-like diabetes and whether it can be treated differently to common forms of diabetes. My work therefore has important implications for individuals with MODY, for the wider diabetes community and is relevant to other genetic disorders.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: The key role of primary cilia in determining tooth morphogenesis
Funder: The Academy of Medical Sciences

Abstract: The loss of teeth not only seriously affects the health of life of patients, but also affects the longevity of elderly people in the long-term. It is one of the most important health problems in the aging society. In the future, the ability to regenerate a tooth as an important digestive organ is a key issue in the field of tissue regeneration and medical health. At present, worldwide scholars are trying to make progress in understanding and promoting tooth development. However, it is worth noting that human teeth are more complex than most animals, including incisors, canines, molars, etc. As an independent organ, how to control the morphology of tooth through development and the principal regulatory mechanisms are still to be disclosed. Therefore, one of the major questions to be answered in this study is how to regulate the development of tooth germs into different morphologies during tooth regeneration, and what the crucial regulatory genes are. More importantly, using this model, this study also helps to understand the principles of morphological control and key molecules in organ regeneration.

Lay Abstract: Tooth formation is highly regulated multistage process, which includes epithelial-mesenchymal signaling interactions, tooth germ development, crown formation and tooth root development. Among these key steps, many key signalings involved are disclosed, such as WNT and HH. However, during tooth formation, which factors could determine the development direction of tooth germ (to molar, premolar or incisor) are still unclear. Primary cilia are organelles on the cell surface as key coordinators of chemical sensation, signal transduction, and control of cell differentiation during tissue development and homeostasis. Recently, several groups including us found that primary cilia could play a significant role in the development of tooth. IFT140, the core member of intraflagellar transport complex A (IFT-A) of primary cilium, is an essential molecule for signal transduction within the primary cilia. By conditional knocking out IFT140 in mesenchymal stem cells in vivo, it is very interesting that the typical molar (multirooted teeth) transformed into an unirooted teeth, which is similar to the shape of human premolar (schematic 1A&B). Based on the previous investigations and our preliminary evaluation of these critical tooth morphological changing in genetic mouse models (delete IFT140 in different stages of DPSCs/odontoblast differentiation by using Prx1-cre/Osx-cre/Dmp1-cre mice), we look forward to exploring the role of primary cilia and core protein IFT140 involved in tooth formation, especially to answer the key mechanism of the development control of complicated tooth shapes from simple shape of tooth germ.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: ORAL AND GASTROINTESTINAL
Award Title: The maternal antibody paradox: Characterising mechanisms and devising solutions for rotavirus vaccination
Funder: Wellcome Trust

Abstract: Maternal antibodies (MA) are transferred to fetus and infant via the placenta and through breast milk, providing protection against pathogens when the immune response is immature. However, MA also suppress the development of B cell responses to pathogens via mechanisms that are not well defined. MA can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus.
 
 
 
Rotavirus infection poses a substantial threat to human health globally. The virus is a major cause of acute gastroenteritis in young children, resulting in ~215,000 deaths each year. Rotavirus vaccines have recently been applied with great success in developed countries, however it is unknown why rotavirus vaccines are much less effective in low-income countries. Whilst malnutrition and the gut microbiome may contribute to poor vaccine efficacy, interference by MA is also considered to be a major prohibitive factor.
 
 
 
This study aims to unravel the mechanisms by which MA limit development of effective antibody responses to rotavirus vaccination in infants. This project also aims to translate mechanistic results into rational design of improved vaccines. This work has the potential to generate vaccines that induce protection against rotavirus in younger children across all economic areas.

Lay Abstract: Antibodies are produced by our immune system to protect against infections. Babies are unable to make antibodies when they are born, so antibodies from the mother (‘maternal antibodies’) are transferred to babies through the placenta and breast milk instead. These maternal antibodies provide protection whilst the child’s immune system develops.

 

However, a downside of maternal antibodies is that they can block vaccines. This is especially concerning for the rotavirus vaccine as rotavirus can cause life-threatening diarrhoea in children. Babies with high maternal antibodies are often not protected against rotavirus disease after vaccination. Despite this problem being identified over twenty years ago, how this occurs is not known.

 

This project aims to work out how maternal antibodies block rotavirus vaccines. This knowledge will then be used to design more effective vaccines, which has the potential to save the lives of infants that would otherwise succumb to rotavirus disease.

Research Activity Codes: 3.4 VACCINES
Health Categories: INFECTION
Award Title: The role of ATRX alterations in the genesis and therapeutic sensitivity of neuroblastoma
Funder: Cancer Research UK

Abstract: Background: Neuroblastoma is a common tumour of childhood, arising in the developing sympathetic nervous system (SNS). In neuroblastoma, genetic alterations in ATRX define a chemo-resistant, poor-outcome group. ATRX has multiple functions including a critical role in the maintenance of genome stability, in addition to a diverse but incompletely understood role in transcriptional regulation. Despite urgent need for novel therapies, the underlying mechanisms driving oncogenesis in ATRX-neuroblastoma are unknown. I will generate developmental models that re-capitulate SNS development to understand how ATRX alterations contribute to neuroblastoma genesis, and identify directly druggable targets arising as a result of transcriptional dysregulation in ATRX mutant cells.

Aims: (1) To generate experimental models that faithfully recapitulate SNS development, and to identify the effects of ATRX-alterations on epigenetic programming/transcriptional regulation during SNS differentiation. (2) To identify the co-operating events that drive oncogenesis in developmental ATRX neuroblastoma models, then to probe the transcriptional landscape of ATRX-neuroblastoma generated in-vivo. (3) To identify and pre-clinically evaluate druggable targets arising as a result of dysregulated transcription in ATRX-neuroblastoma.

Methods: (1) I will perform ChIP-sequencing, ATAC-sequencing and RNA-sequencing in isogenic ATRX-mutant/wild-type induced pluripotent stem cells at different stages of SNS development, to identify dynamic genome-wide changes in epigenetic regulation during SNS development, and how these contribute to oncogenesis. (2) I will investigate the tumorigenic potential of ATRX alterations alone, and following induction of chromosomal instability. Based on clinical sequencing data, I will also evaluate whether activating ALK mutations co-operate with ATRX alterations to drive oncogenesis. (3) Based on my published and preliminary data I will focus on combination therapies targeting both transcriptional activation and DNA damage repair pathway vulnerabilities, arising as a result of ATRX alterations.

How the results of this research will be used: This research will result in greater insight into the origins of ATRX-neuroblastoma and identify druggable targets and novel combination therapies for this poor outcome group. This will ultimately lead to a programme of laboratory work that will in-turn be translated into innovative clinical trials for children with currently incurable neuroblastoma.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: The role of Agrin loss in the establishment and treatment of OA pain
Funder: Versus Arthritis

Abstract: Blocking non-specific pain mechanisms in osteoarthritis such as inhibiting NGF or TrkA improved pain however, in some patients, induced accelerated osteoarthritis (Hochberg, 2015).

There is a need for targets that are specific to osteoarthritis-related pain mechanisms, to pathological pain, and ideally which also improve cartilage health and homeostasis.

New data from our laboratory and data from the literature suggest that the loss of the proteoglycan Agrin in cartilage and in sensory nerves underpins both cartilage loss and establishment of allodynia in OA and that agrin supplementation will block pathological pain in OA while also inducing cartilage regeneration.

Agrin loss in the dorsal root ganglia (DRG) and in the spinal cord dorsal horns (DH) is a general and critical mechanism in neuropathic pain (Cui and Bazan, 2010). Neuropathic pain is highly prevalent in osteoarthritis and is associated with worse quality of life (Valdes et al., 2014). Agrin supplementation removed neuropathic pain in animal models (Cui and Bazan, 2010). We discovered that Agrin is a potent chondrogenic factor and is lost in osteoarthritic cartilage (Eldridge et al., 2015), at least in part through proteolysis. As in other models of neuropathic pain, we demonstrated downregulation of agrin in the ipsilateral DRG of mice which had developed pain post surgical-induction of osteoarthritis. C-terminal agrin fragments induce axon growth (Bergstrom et al., 2007; Kim et al., 2007; Mantych and Ferreira, 2001), thereby possibly contributing to the invasion of nociceptive nerves observed in osteoarthritic cartilage (Bowyer et al.). We hypothesize that agrin loss within the joint, the DRG and the DH is a common mechanism which links cartilage breakdown to the establishment of neuropathic pain in osteoarthritis and that restoration of agrin expression, inhibition of agrin proteolysis or agrin supplementation will reduce neuropathic pain whilst also providing a chondroprotective or even chondro-regenerative effect.

In this application we will study:

1) Whether and how C-terminal Agrin degradation products within cartilage contribute to the nociceptive nerve invasion in cartilage in humans and animal models of osteoarthritis;

2) The mechanisms of agrin loss in cartilage, DRG and DH in osteoarthritis;

3) Whether restoration of agrin expression in the DRG, DH and cartilage, using tissue specific transgenics, will decrease neuropathic pain in osteoarthritis models.

These studies will further our understanding of the mechanisms of pathological pain in osteoarthritis and will identify, for the first time, a pharmaceutical target that will simultaneously tackle symptoms and structural outcomes; thereby overcoming the limitations of targeting non-specific pain mechanisms.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: MUSCULOSKELETAL