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）：该提案设想了一种基于新发现的可药物酶的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 积累的核心作用 (1)，但存在。迫切需要进一步了解导致散发性 AD 中 Aβ 增加的机制。此外，AD 病理学的许多方面不能简单地理解为 Aβ 积累的结果，并表明其他分子机制有助于促进 Aβ 的积累。还非常需要能够与发病机制合理联系的诊断方法，这些挑战是该领域众所周知的。建立在控制大脑发育中几个最重要的信号通路的新型酶家族的发现基础上，该酶家族催化将一类细胞外蛋白与细胞表面连接的磷酸二酯键的裂解 (2)。作为Notch、音刺猬、成纤维细胞生长因子、Wnt、肝配蛋白 (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 在神经退行性变中的作用是偶然发现的。成人大脑中 GDE 的条件性缺失会导致深刻的、年龄依赖性的神经退行性变化，其中包括人类神经退行性的许多特征我们发现 GDE 功能的丧失会导致人类神经退行性疾病，该方法利用了 GDE 活性的幸运结果，即将底物蛋白释放到细胞外区室和脑脊液中，从而创建了 GDE 活性的“生物标志物”。根据这一概念，我们确定朊病毒蛋白是 GDE 的底物，在人类 AD 受试者的脑脊液中，朊病毒蛋白的水平随认知能力下降而降低(3)，最近的研究表明朊病毒蛋白与认知能力下降有关。 AD 中的突触强度和增强的 Aβ 生成 (4, 5) 我们将使用无偏见的方法来扩展这一先例，以识别正常人和患病人类的脑脊液和大脑中的 GDE 底物，这些生物标志物将识别 GDE 功能所导致的特定信号通路。如果成功的话，这种方法将提供与 GDE 通路调节剂相结合的机制相关的疾病生物标志物，作为新的基于机制的 AD 诊断和治疗方法。