NIHRDataInsights/HRCSData huggingface dataset:
Title: The Sigma 1 receptor and ER-mitochondria signaling in fronto-temporal dementia
Funder: Alzheimer's Research UK

Abstract: Fronto-temporal dementia (FTD) is a common form of dementia. As with other types of dementia, there are no cures or effective disease-modifying treatments for FTD. One problem scientists have in designing treatments for FTD is that it involves damage to many nerve cell functions and so it is unclear which damaged function should be targeted for therapy. However, many of these damaged functions are controlled by communications that two nerve cell structures make with each other. These structures are mitochondria and the endoplasmic reticulum (ER). We have shown that ER-mitochondria communications are disrupted in FTD and identified a mechanism underlying this damage. Thus, the many nerve cell functions damaged in FTD may be linked to damage to ER-mitochondria communications. The Sigma-1 receptor is a protein that is known to function in ER-mitochondria communications. Moreover a drug that affects Sigma-1 receptor function is being trialled in Alzheimer’s disease patients. This project is to investigate the Sigma-1 receptor in FTD and to see whether one of the Sigma-1 receptor drugs might be beneficial in FTD.

Lay abstract: Fronto-temporal dementia (FTD) is a common form of dementia. As with other types of dementia, there are no cures or effective disease-modifying treatments for FTD. One problem scientists have in designing treatments for FTD is that it involves damage to many nerve cell functions and so it is unclear which damaged function should be targeted for therapy. However, many of these damaged functions are controlled by communications that two nerve cell structures make with each other. These structures are mitochondria and the endoplasmic reticulum (ER). We have shown that ER-mitochondria communications are disrupted in FTD and identified a mechanism underlying this damage. Thus, the many nerve cell functions damaged in FTD may be linked to damage to ER-mitochondria communications. The Sigma-1 receptor is a protein that is known to function in ER-mitochondria communications. Moreover a drug that affects Sigma-1 receptor function is being trialled in Alzheimer’s disease patients. This project is to investigate the Sigma-1 receptor in FTD and to see whether one of the Sigma-1 receptor drugs might be beneficial in FTD.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: 123I-MIBG Scintigraphy Utility as a biomarker for Prodromal DEmentia with Lewy Bodies (SUPErB)
Funder: Alzheimer's Research UK

Abstract: Early and accurate identification of dementia is a major priority and will require diagnosis during the mild cognitive impairment (MCI) stage preceding dementia, also known as the prodromal phase. Biological markers of disease (biomarkers) will be needed to make these early diagnoses accurately but, unlike Alzheimer’s disease, we know little about the prodromal stage of dementia with Lewy bodies (DLB). DLB, like Alzheimer’s disease, has excellent biomarkers but they have not been investigated in the prodromal stage. Our pilot study has however demonstrated the feasibility of identifying people with pDLB. We have found that people with prodromal DLB have abnormal dopaminergic imaging consistent with underlying Lewy body pathology. However, pathological studies have shown that an early change in DLB is outside the brain, involving loss of nerve projections to the heart at very early stages. Myocardial tracer (123I-MIBG) imaging assesses these nerve projections and so there is good reason to believe that it may be a better early biomarker of pDLB than dopaminergic brain imaging. This proposal is for a five year study examining the utility of MIBG imaging as a biomarker predictor of cognitive decline and conversion to dementia in people with MCI due to prodromal DLB.

Lay abstract: Early and accurate identification of dementia is a major priority and will require diagnosis during the mild cognitive impairment (MCI) stage preceding dementia, also known as the prodromal phase. Biological markers of disease (biomarkers) will be needed to make these early diagnoses accurately but, unlike Alzheimer’s disease, we know little about the prodromal stage of dementia with Lewy bodies (DLB). DLB, like Alzheimer’s disease, has excellent biomarkers but they have not been investigated in the prodromal stage. Our pilot study has however demonstrated the feasibility of identifying people with pDLB. We have found that people with prodromal DLB have abnormal dopaminergic imaging consistent with underlying Lewy body pathology. However, pathological studies have shown that an early change in DLB is outside the brain, involving loss of nerve projections to the heart at very early stages. Myocardial tracer (123I-MIBG) imaging assesses these nerve projections and so there is good reason to believe that it may be a better early biomarker of pDLB than dopaminergic brain imaging. This proposal is for a five year study examining the utility of MIBG imaging as a biomarker predictor of cognitive decline and conversion to dementia in people with MCI due to prodromal DLB.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Oral Ketamine Capsules - A new potential treatment for Depression. A pharmacokinetic and pharmacodynamic assessment of Ketamine and Metabolites in a dose-escalating, placebo-controlled clinical trial in healthy subjects.
Funder: Wellcome Trust

Abstract: Neurocentrx has developed oral capsule formulations of Ketamine, aiming to be new treatments for Depression. Ketamine is a synthetic drug created in the 1960’s. It is on the “essential medicine” list of the World Health Organisation (WHO), approved and licensed by health regulators worldwide as an injectable anaesthetic. More recently, and at sub-anaesthetic doses, clinical trials have shown that some patients with depression have a rapid response to injectable ketamine (hours or days). Most other anti-depressant medicines take many weeks to work. no oral ketamine products are currently available as a licensed medicine worldwide. Our project will assess oral capsules in healthy people in a clinical trial. We will assess absorption and excretion with increasing doses of drug and measure any side-effects. These data will be essential to accurately plan trials in depression patients where we will then look for benefits. Oral capsules could be used at home, and are hoped to be a cheaper treatment option, with fewer side-effects for patients. The summary above may be amended from time to time by mutual agreement of the Parties. For this clause agreement by email will be sufficient to render a valid amendment to the summary).

Lay abstract: Ketamine is a synthetic drug created in the 1960’s. It is on the “essential medicine” list of the World Health Organisation (WHO), approved and licensed by health regulators world-wide as an injectable anaesthetic. More recently, and at sub-anaesthetic doses, clinical trials have shown that some patients with depression have a rapid response to ketamine (hours or days). Most anti-depressant medicines take many weeks to work. Some patients are “treatment-resistant” (TRD) meaning that these standard medications do not seem to work. A nasal Ketamine spray has recently been approved for TRD. However nasal sprays have problems: coordination issues, a hit-like effect, inconsistency of delivery, nausea and vomiting. Spray containers are also more costly and less environmentally friendly. Oral delivery could solve some of these issues and reduce others. Neurocentrx has developed oral capsule formulations of Ketamine. no oral ketamine products are currently available as a licensed medicine worldwide. Our project will assess oral capsules in healthy people in a clinical trial. We will assess absorption and excretion with increasing doses of product and measure any side-effects. These data will be essential to accurately plan trials in patients with mood disorders where we will look for benefits to depression episodes.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Correcting lysosomal and autophagy dysfunction as a therapeutic strategy for Alzheimer's disease
Funder: Alzheimer's Research UK

Abstract: The main focus of the proposed study is on the lysosomal and autophagy pathway, which acts like a ‘garbage disposal’ system within the brain cells that remove and recycle damaged material to prevent the build-up of toxic waste. Early and progressive disruption of these cellular functions plays a central role in Alzheimer’s disease (AD) development and represents a prime target for innovative therapies for AD. In the proposed study, I plan to use human-derived stem cells together with cutting-edge genome-editing techniques to investigate the manner in which genetic risk factors for AD disrupt this garbage disposal system. I have developed a way to generate human brain cells (disease-in-a-dish) from human-derived stem cells that carry genomes of AD patients. This technology rewinds the biological clock of the cell and provides a means of observing how AD develops in the human brain, thus revealing the onset of the disease at a cellular level that can take decades to manifest in patients. The proposed study addresses the molecular mechanisms of AD and could lead to new potential drug targets to prevent, halt or reverse the symptoms of the disease.

Lay abstract: The main focus of the proposed study is on the lysosomal and autophagy pathway, which acts like a ‘garbage disposal’ system within the brain cells that remove and recycle damaged material to prevent the build-up of toxic waste. Early and progressive disruption of these cellular functions plays a central role in Alzheimer’s disease (AD) development and represents a prime target for innovative therapies for AD. In the proposed study, I plan to use human-derived stem cells together with cutting-edge genome-editing techniques to investigate the manner in which genetic risk factors for AD disrupt this garbage disposal system. I have developed a way to generate human brain cells (disease-in-a-dish) from human-derived stem cells that carry genomes of AD patients. This technology rewinds the biological clock of the cell and provides a means of observing how AD develops in the human brain, thus revealing the onset of the disease at a cellular level that can take decades to manifest in patients. The proposed study addresses the molecular mechanisms of AD and could lead to new potential drug targets to prevent, halt or reverse the symptoms of the disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of tau in synapse survival and its relevance to Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: In Alzheimer’s disease (AD), the loss of synapses, vital communication points between nerve cells, is thought to be the driving force behind memory loss. In AD, and related disorders such as frontotemporal dementia, tau, a normal protein found inside nerve cells, becomes “stickier”, clumping together to eventually form large aggregates called tangles. “Sticky” tau can damage synapses but evidence suggests “normal” tau is also needed to keep synapses healthy. Tau clumping may therefore be a double-edged sword; turning tau toxic whilst simultaneously preventing its normal function. Using thin slices of brain kept alive in culture dishes, we will investigate the role of normal tau in keeping synapses healthy and how this changes in AD. These slice cultures, which contain the different cell types and synapses found in an intact brain, allow us to easily test drugs and examine the sequence of changes in living tissue. This complements work in post-mortem brains, which provide a useful snapshot at the end-stages of the disease. This will help us to understand what aspects of synapse damage in AD are caused by loss of normal tau function and enable us to design and refine therapies that provide the best outcome for synapses.

Lay abstract: In Alzheimer’s disease (AD), the loss of synapses, vital communication points between nerve cells, is thought to be the driving force behind memory loss. In AD, and related disorders such as frontotemporal dementia, tau, a normal protein found inside nerve cells, becomes “stickier”, clumping together to eventually form large aggregates called tangles. “Sticky” tau can damage synapses but evidence suggests “normal” tau is also needed to keep synapses healthy. Tau clumping may therefore be a double-edged sword; turning tau toxic whilst simultaneously preventing its normal function. Using thin slices of brain kept alive in culture dishes, we will investigate the role of normal tau in keeping synapses healthy and how this changes in AD. These slice cultures, which contain the different cell types and synapses found in an intact brain, allow us to easily test drugs and examine the sequence of changes in living tissue. This complements work in post-mortem brains, which provide a useful snapshot at the end-stages of the disease. This will help us to understand what aspects of synapse damage in AD are caused by loss of normal tau function and enable us to design and refine therapies that provide the best outcome for synapses.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating Genetic Risk in Dementia
Funder: Alzheimer's Research UK

Abstract: Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Lewy body dementia (LBD) are the most common causes of dementia leading to loss of memory and thoughts and other symptoms. Scientists know that changes in proteins in these diseases cause them to buildup inside brain cells eventually resulting in them dying. Scientists have also discovered that changes in genes can increase the risk of a person getting dementia, but we do not know how these genetic changes may affect the buildup of these proteins to cause dementia. In this project I plan to investigate how several of these genetic risks impact the protein buildup and how they affect the death of brain cells. I will do this using a system that I have developed where I keep small sections of mouse brain tissue alive that develop the buildup of these proteins like in disease. By using this model I can accelerate our understanding of how these genetic risk factors affect protein buildup and brain cell death and then expand these studies into animal models of the disease to predict if people with dementia can be helped in the future by targeting this protein accumulation or these genetic pathways.

Lay abstract: Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Lewy body dementia (LBD) are the most common causes of dementia leading to loss of memory and thoughts and other symptoms. Scientists know that changes in proteins in these diseases cause them to buildup inside brain cells eventually resulting in them dying. Scientists have also discovered that changes in genes can increase the risk of a person getting dementia, but we do not know how these genetic changes may affect the buildup of these proteins to cause dementia. In this project I plan to investigate how several of these genetic risks impact the protein buildup and how they affect the death of brain cells. I will do this using a system that I have developed where I keep small sections of mouse brain tissue alive that develop the buildup of these proteins like in disease. By using this model I can accelerate our understanding of how these genetic risk factors affect protein buildup and brain cell death and then expand these studies into animal models of the disease to predict if people with dementia can be helped in the future by targeting this protein accumulation or these genetic pathways.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: CCR5 modulation and autophagy
Funder: Alzheimer's Research UK

Abstract: Most neurodegenerative diseases manifest with the accumulation of proteins in clumps within neurons/nerve cells. Such proteins, like mutant huntingtin (in Huntington’s disease) and mutant tau (in various dementias), are poisonous to cells and cause their death. My laboratory discovered that a process in the cells called autophagy is critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including mutant huntingtin and mutant tau. Recent studies have highlighted the possible deleterious roles in neurodegeneration mediated by glial cells, which normally support the neurons in the brain. For example, chemicals called cytokines released from one type of glia appear to contribute to neurodegeneration in Alzheimer’s and Parkinson’s disease. Our recent data have led us to hypothesise that the cytokines, CCL3, CCL4 and CCL5, inhibit neuronal autophagy by binding and activating their receptor, CCR5. Furthermore, our preliminary data suggest that CCR5 inhibition may induce autophagy. We aim to perform robust validation of this mechanism and test if CCR5 inhibition may ameliorate neurodegenerative diseases in mouse models via autophagy induction, as this would provide novel insights into disease mechanisms and tractable opportunities for developing drugs for this target.

Lay abstract: Most neurodegenerative diseases manifest with the accumulation of proteins in clumps within neurons/nerve cells. Such proteins, like mutant huntingtin (in Huntington’s disease) and mutant tau (in various dementias), are poisonous to cells and cause their death. My laboratory discovered that a process in the cells called autophagy is critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including mutant huntingtin and mutant tau. Recent studies have highlighted the possible deleterious roles in neurodegeneration mediated by glial cells, which normally support the neurons in the brain. For example, chemicals called cytokines released from one type of glia appear to contribute to neurodegeneration in Alzheimer’s and Parkinson’s disease. Our recent data have led us to hypothesise that the cytokines, CCL3, CCL4 and CCL5, inhibit neuronal autophagy by binding and activating their receptor, CCR5. Furthermore, our preliminary data suggest that CCR5 inhibition may induce autophagy. We aim to perform robust validation of this mechanism and test if CCR5 inhibition may ameliorate neurodegenerative diseases in mouse models via autophagy induction, as this would provide novel insights into disease mechanisms and tractable opportunities for developing drugs for this target.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modulation of astrocytic gap junction coupling in focal epilepsy
Funder: Wellcome Trust

Abstract: Understanding the mechanisms that underlie epileptogenesis is crucial for the development of new treatments. Recent evidence has implicated astrocytes as a key cell population in the aetiology of focal epilepsy. Astrocytic gap-junction networks perform vital functions in supporting neural activity, including the shuttling of essential metabolic fuels and the regulation of the extracellular ionic environment for neurons. The objective of this project is to understand the relationship between neuronal activity and astrocytic gap-junction coupling, and how this relationship may break down in epilepsy. This will build upon preliminary evidence that astrocytic gap-junctions can show rapid, activity-dependent changes, in a manner related to levels of neuronal activity. The work will use surgically-resected human brain tissue and mouse models in which it is possible to selectively manipulate defined cell types. There are three parallel research aims. First, glioma-associated brain tissue will be used as a test case to relate functional astrocytic gap-junction coupling and neuronal hyperexcitability in a human context. Second, in vivo optical studies in mouse will examine how epileptiform network activity influences dynamic astrocytic gap-junction coupling. And third, optogenetic and pharmacological strategies will be used to dissect the cellular mechanisms that mediate activity-dependent changes in astrocytic coupling.

Lay abstract: Epilepsy is a common, debilitating disease in which short attacks of abnormal brain activity produce seizures. One of the most frequent causes of epilepsy is when a lesion, for instance a tumour, disturbs a brain area and causes nearby tissue to become more excitable. However, we do not understand how different cell types contribute to this process. My research will focus on a particular population of cells called astrocytes, which normally provide energy to nerve cells and remove their waste products. Astrocytes form large networks as they are interconnected by channels called gap junctions, and I will test the hypothesis that these gap junctions are abnormally regulated in epilepsy. To study this, I will use brain tissue removed from patients undergoing surgery and also rodent experimental models of epilepsy. The research will advance our understanding of how astrocytes contribute to epilepsy and will identify new ways to improve our treatments.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Non-canonical regulation of cAMP-dependent protein kinase in the synapse
Funder: Wellcome Trust

Abstract: This project will investigate a mechanism for regulating cAMP-dependent protein kinase (PKA) that is not founded on cAMP fluctuations. Neuronal PKA activity is largely dictated by rates of binding and release of PKA catalytic subunits from inhibitory type II regulatory (RII) subunits. The balance of these rates determines the fraction of free catalytic subunits. According to the canonical model, reductions in PKA activity follow from decreases in cAMP concentration since cAMP-free RII subunits bind catalytic subunits with higher affinity. Dephosphorylation of a serine in the RII autoinhibitory sequence also generates a form of RII with higher affinity for catalytic subunits, but no plausible mechanism has been uncovered that involves regulation of this site. We will investigate whether anchoring of phosphatases in complex with RII subunits enables suppression of PKA activity by shifting the Michaelis constant for RII dephosphorylation into the physiological range. We will build and test models of neuronal PKA signalling to understand the kinetic basis of this mode of PKA regulation. We will examine whether RII dephosphorylation within a synaptic signalling complex is necessary for the induction of long-term depression of synaptic strength. Finally, we will investigate interplay between Ca2+ signalling and this novel form of PKA regulation.

Lay abstract: This project will focus on the enzyme Protein Kinase A (PKA) that regulates cellular processes throughout the body including rates of heart muscle contraction and pancreatic insulin release. PKA is the major intracellular receptor for cyclic AMP. This second messenger binds to inhibitory PKA regulatory subunits and activates the enzyme by decreasing PKA catalytic subunit capture. We will investigate a new mechanism for decreasing PKA activity that may occur in multi-protein assemblies that contain both PKA and phosphatases. We will investigate this non-classical form of PKA regulation in three ways. First, we will build computational models of this new mechanism and test these using test tube enzyme assays. Second, we will determine whether PKA activity is suppressed in this way to bring about long-term decreases in synaptic strength, an important component of learning and memory. Third, we will explore how Ca2+ fluctuations are linked to this form of PKA regulation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL