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Current Tissue Access Projects


Title

Pilot study of the role of spleen tyrosine kinase in pathobiology of repetitive mild TBI

Principal Investigator

Fiona Crawford, PhD

CEO & President

Roskamp Institute

Abstract

We have identified a novel molecular target (Spleen Tyrosine Kinase, Syk) for Alzheimer’s disease, inhibition of which, by the compound Nilvadipine, results in mitigation of amyloid, tau and neuroinflammatory pathology in mouse models of Alzheimer’s disease.  Nilvadipine was demonstrated to reduce Alzheimer’s cognitive decline in early stage Alzheimer’s patients in a Phase III trial.  We have tested Nilvadipine in our mouse models of repetitive mild TBI and shown reduction in neuroinflammation and tau pathology, as well as improvement in cognitive outcomes.  We therefore wish to determine the relevance of our findings to the human TBI patient population by determining if Syk or related Syk signaling molecules can be detected in the brains of TBI patients versus controls.

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Title

TDP-43 proteinopathy in traumatic brain injury related neurodegeneration (TReND)

Principal Investigator

William Stewart, MBChB, PhD

Consultant Neuropathologist

University of Glasgow, Department of Neuropathology

Abstract

Traumatic brain injury (TBI) is a risk factor for dementia and related degenerative brain diseases. Pathology studies of the brains of people with a history of TBI show a range of abnormalities. Among these, abnormal deposition of a protein known as TDP-43 has been described. However, this abnormal TDP-43 protein can also be found in many other degenerative brain diseases. To date it remains uncertain whether the TDP-43 abnormalities in patients with TBI are unique or are simply a reflection of other, coincident pathologies.

In this study, we will investigate the pattern and distribution of TDP-43 protein deposition in patients with a history of TBI. We will then compare our findings in patients with TBI to the deposition of TDP-43 in normal aging and other degenerative brain diseases. This will give us a picture of the effect of TBI on TDP-43 deposition which might help our understanding of the link between brain injury and dementia.

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Title

Single Nucleus Transcriptomics in Chronic TBI

Principal Investigator

Victoria E. Johnson, MBChB, PhD

Assistant Professor

University of Pennsylvania, Department of Neurosurgery

Abstract

Moderate or severe traumatic brain injury (TBI) is a substantial health problem that In addition to often devastating acute effects, can trigger complex chronic pathologies. In a subset of individuals, progressive loss of both the grey and white matter in the brain has been observed following moderate or severe TBI, in some cases persisting many months and years after injury. However, the processes occurring that drive this chronic degeneration are unknown. By examining post-mortem brain tissue from individuals both with and without progressive degeneration after TBI, we aim to perform a detailed examination of the function of cells in the brain.

We will achieve this using single cell RNA sequencing -a technique that permits us to identify the genes that each individual cell is expressing. This will allow us to identify the specific ways in which cells in the brain degenerate over time. Understanding these processes may help elucidate potential pathways that can be targeted to prevent progressive degeneration following TBI.

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Title

Single Nucleus Transcriptomics in Chronic TBI

Principal Investigator

Victoria E. Johnson, MBChB, PhD

Assistant Professor

University of Pennsylvania, Department of Neurosurgery

Abstract

Moderate or severe traumatic brain injury (TBI) is a substantial health problem that In addition to often devastating acute effects, can trigger complex chronic pathologies. In a subset of individuals, progressive loss of both the grey and white matter in the brain has been observed following moderate or severe TBI, in some cases persisting many months and years after injury. However, the processes occurring that drive this chronic degeneration are unknown. By examining post-mortem brain tissue from individuals both with and without progressive degeneration after TBI, we aim to perform a detailed examination of the function of cells in the brain.

We will achieve this using single cell RNA sequencing -a technique that permits us to identify the genes that each individual cell is expressing. This will allow us to identify the specific ways in which cells in the brain degenerate over time. Understanding these processes may help elucidate potential pathways that can be targeted to prevent progressive degeneration following TBI.

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Title

Defining Hypo N-Glycosylation following TBI

Principal Investigator

Douglas A. Andres, PhD

University of Kentucky College of Medicine, Department of Molecular & Cellular Biochemistry

Abstract

N-linked protein glycosylation is a cellular process that decorates a large number of proteins with chains of sugar molecules within the human body. The process is highly regulated and results in a unique glycan profile for each cell in the brain, with N-glycosylated proteins known to regulate key brain processes including learning and memory formation. Furthermore, aberrant N-glycosylation results in neuroinflammation and neuronal cell death. Using a mouse model of traumatic brain injury (TBI) we performed an analysis of global changes in N-linked glycans using cutting edge technology. These data demonstrate that TBI results in defects in glycosylation and suggest that dysregulation of this process could be one of the underpinnings of TBI pathophysiology. We wish to determine whether similar N-glycosylation alterations occur within the injured human brain following traumatic brain injury.