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GDE and Neurodegenerative Diseases

GDE 和神经退行性疾病

基本信息

批准号：
8929146
负责人：
SHANTHINI SOCKANATHAN
金额：
$ 31.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8929146
关键词：
Address Adult Affinity Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Asses Astrocytes Astrocytosis Biochemical Biological Assay Biological Markers Body Fluids Brain California Cell surface Cells Ciliary Neurotrophic Factor Receptor Collection Cytosol Data Development Diagnostic Disease Enzymes Ephrins Erinaceidae Extracellular Protein FDA approved Family Fibroblast Growth Factor GPI Membrane Anchors Generations Genetic Genetic Models Glycosylphosphatidylinositol Linkage Glycosylphosphatidylinositols Glypican Goals Health Human Impaired cognition Individual Inflammation Interruption Lewy Body Dementia Link Malignant Neoplasms Mass Spectrum Analysis Measures Membrane Methods Microglia Molecular Motor Neurons Mus Nerve Degeneration Neurodegenerative Disorders Neurons Oligodendroglia Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Primary carcinoma of the liver cells Prion Diseases Prions Process Proteins Publishing Reagent Research Role Sampling Serum Signal Pathway Signal Transduction Spinal Cord Surface Synapses Testing Therapeutic Tissue Sample Tissues Transgenes Ubiquitin Universities Work abeta accumulation age related aged base brain tissue candidate marker clinical Diagnosis cognitive function cohort contactin extracellular glucagon-degrading enzyme glycerophosphodiester phosphodiesterase hippocampal atrophy human disease human subject inhibitor/antagonist link protein meetings member mouse model neurofilament neuropathology neurotrophic factor notch protein novel oncology phosphodiester postnatal protein expression small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This proposal imagines a paradigm shift for understanding human Alzheimer's disease that is based on a newly discovered, druggable enzyme. Our current understanding of AD proposes a central role for the accumulation of amyloid Aβ (1), but there is great need for advances in understanding mechanisms that cause increases of Aβ in sporadic AD. Moreover, there are many aspects of the pathology of AD that cannot be simply understood as a consequence of Aβ accumulation, and suggest other molecular mechanisms contribute to pathogenesis. There is also a great need for diagnostics that can be rationally linked to pathogenesis. Most of all there is a need for effective therapeutics. These challenges are well known to the field. We see a unique opportunity to advance AD research that builds on the discovery of a novel enzyme family that controls several of the most important signalling pathways in brain development. GDEs catalyze cleavage of the phosphodiester bond that links a class of extracellular proteins to the cell surface (2). These GPI-linked proteins act as activators or inhibitors of Notch, sonic hedgehog, fibroblast growth factor, Wnt, ephrin (EphA5), ciliary neurotrophic factor receptor (CNTF), glial derived neurotrophic factor, and contactins. The role of GDEs in neurodegeneration was made serendipitously with the discovery that conditional deletion of GDE in adult brain results in profound, age-dependent neurodegenerative changes that include many of the hallmarks of human neurodegenerative disease. We hypothesize that loss of GDE function contributes to human neurodegenerative disease. The approach exploits the fortunate consequence of GDE activity, which is to shed substrate proteins into the extracellular compartment and CSF. This creates "biomarkers" of GDE activity. As proof of concept, we have determined that prion protein is a substrate of GDE. Prion protein is present in the CSF at levels that are reduced in human AD subjects in parallel with cognitive decline(3), and recent studies implicate prion protein in pathological reduction of synaptic strength and enhanced Aβ generation in AD(4, 5). We will expand this precedent using non-biased methods to identify GDE substrates in CSF and brain of normal and diseased humans. These biomarkers will identify specific signalling pathways consequent to GDE function that are consistently disrupted in AD. Where successful, this approach will provide mechanism-linked biomarkers of disease that can be combined with modulators of the GDE pathway as new mechanism-based diagnostics and therapeutics for AD.