GDE and Neurodegenerative Diseases

GDE 和神经退行性疾病

• 批准号: 8798112
• 负责人: SHANTHINI SOCKANATHAN
• 金额: $ 32.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8798112
• 关键词: Address; Adult; Affinity; Age; Alzheimer' 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; Goals; 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; glypican 3; 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; public health relevance; small molecule; therapeutic target

 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.

 描述(由申请人提供)：这项提案设想了一种基于新发现的可药物酶的理解人类阿尔茨海默氏病的范式转变。我们目前对AD的理解提出了淀粉样蛋白Aβ(1)积累的中心作用，但在理解导致散发性AD中Aβ增加的机制方面仍有很大的需要。此外，AD的许多病理方面不能简单地理解为Aβ积聚的结果，并提示其他分子机制参与了发病机制。也非常需要能够合理地与发病机制联系起来的诊断方法。最重要的是，需要有效的治疗方法。这些挑战对该领域来说是众所周知的。我们看到了一个独特的机会来推进AD研究，该研究建立在一种新的酶家族的发现上，该家族控制着大脑发育中几个最重要的信号通路。GDES催化将一类细胞外蛋白质连接到细胞表面的磷酸二酯键的裂解(2)。这些与GPI连接的蛋白可作为Notch、Sonic Hedgehog、成纤维细胞生长因子、Wnt、ephin(EPHA5)、睫状神经营养因子受体(CNTF)、胶质源性神经营养因子和接触素的激活剂或抑制剂。GDE在神经退行性疾病中的作用是偶然发现的，即成人大脑中GDE的有条件缺失会导致深刻的、年龄相关的神经退行性变化，包括人类神经退行性疾病的许多特征。我们假设GDE功能的丧失与人类神经退行性疾病有关。这种方法利用了GDE活性的幸运结果，即将底物蛋白质释放到细胞外隔室和脑脊液中。这就产生了GDE活性的“生物标志物”。作为概念的证明，我们已经确定Pron蛋白是GDE的底物。在人类AD患者中，脑脊液中的Prion蛋白的水平与认知能力下降的水平平行(3)，最近的研究表明，Prion蛋白与AD患者突触强度的病理性降低和A-β的生成增加有关(4，5)。我们将使用无偏见的方法扩展这一先例，以确定正常和疾病人类脑脊液和脑中的GDE底物。这些生物标志物将识别在AD中持续中断的GDE功能所导致的特定信号通路。如果成功，这种方法将提供机制相关的疾病生物标记物，可以与GDE途径的调节器相结合，作为新的基于机制的AD诊断和治疗方法。