Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias

阿尔茨海默病α-突触核蛋白菌株研究中心

• 批准号: 10373915
• 负责人: VIRGINIA M LEE
• 金额: $ 362.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373915
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Archives; Area; Autopsy; Bioinformatics; Biological; Biological Markers; Biological Models; Biometry; Blood; Caring; Cells; Cessation of life; Clinical; Cognition; Cognitive; Collaborations; Complement; Cytoplasmic Inclusion; DNA; Data; Dementia; Dementia with Lewy Bodies; Diagnosis; Disease; Disease Management; Functional disorder; Genetic Markers; Goals; Guidelines; Heterogeneity; Image; Impaired cognition; In Vitro; Lead; Lewy Bodies; Lewy Body Dementia; Lewy neurites; Link; Measures; Mediating; Molecular; Monoclonal Antibodies; Multiple System Atrophy; National Institute on Aging; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathology; Patients; Pennsylvania; Preparation; Principal Investigator; Proteins; RNA; Recommendation; Research Personnel; Research Priority; SNP array; Science; Structure; Technology; Tissues; Universities; Vision; Work; alpha synuclein; alpha synuclein gene; behavioral impairment; biomarker development; data management; design; disease heterogeneity; disease phenotype; drug discovery; in vivo; medical schools; meetings; mixed dementia; neuropathology; new therapeutic target; novel; novel therapeutics; precision medicine; programs; progressive neurodegeneration; symposium; synucleinopathy; targeted biomarker; transmission process

National Institute on Aging (NIA) Penn U19 “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias”. Principal Investigator: John Q. Trojanowski Center Summary/Abstract: This U19 Center pursues research priorities in the “Recommendations of the Alzheimer's disease-related dementias conference”.13 It especially focuses on priorities that address Alzheimer's disease (AD) and related dementias (ADRD) in topic areas of multiple etiology dementias, Lewy body (LB) dementias (LBD), including dementia with LBs (DLB) and Parkinson's disease without (PD) and with dementia (PDD), new guidelines on the biological definition of AD14-17 and reflects recommendations from a recent NIA meeting on “Neurodegenerative Disease Transmissibility: Current Science and Recommendations for Future Research” (Frosch M et al, in preparation, 2018). Among ADRD, AD with abundant LB co-pathology is the most common subtype of AD. We hypothesize that accumulations of pathological aSyn lead to neuron dysfunction and death due to misfolding and transmission of different strains of pathological aSyn to form LBs and LNs and that aSyn and AD pathology interact to modify the distribution of each other and contribute to behavioral impairments. To accomplish these goals, Projects I and II complement each other and Projects III and IV by seeking to elucidate aSyn strains underlying AD+aSyn/LBD compared to PD, Multiple system atrophy (MSA) is studied as a control because it is characterized by aSyn glial cytoplasmic inclusions (GCIs) that are comprised of a distinct aSyn strain which is more potent than LBD or AD+aSyn strains of pathological aSyn. In parallel, Project III analyzes regional AD/LBD neuropathology with novel monoclonal antibodies (mAbs) to correlate these data with diverse cognitive difficulties and structural imaging. A 2X2 design is used that contrasts clinical AD phenotypes and primary AD pathologies. This is complemented by Project IV which measures cognition, blood and cerebrospinal (CSF) biomarkers, including aSyn, as well as SNP arrays, to better understand, diagnose and manage diverse clinical manifestations of AD/LBD in order to advance towards a precision medicine approach for care and disease management. The landmark discoveries of aSyn gene (SNCA) alterations pathogenic for LBD and that pathological aSyn is the disease protein in synucleinopathies, in addition to the cell-to-cell spread of aSyn strains, places aSyn at center stage for understanding mechanisms of AD+aSyn and LBD. This Penn U19 Center addresses these key issues in four Projects supported by four Cores. Moreover, this Center also will work with NIA to provide biofluids, DNA/RNA, autopsy tissue and data collected from ADRD patients over the past 20 years at Penn in addition to aSyn strains to qualified investigators. By addressing the hypothesis that distinct aSyn strains underlie AD+aSyn/LBD, we will clarify the molecular basis of heterogeneity in AD+aSyn/LBD while opening up new targets for drug discovery and biomarker development in at the Penn U19 Center in collaboration with NIA program.

国家衰老研究所 (NIA) Penn U19“阿尔茨海默病和阿尔茨海默病中的 α-突触核蛋白菌株中心” 相关痴呆症”首席研究员：John Q. Trojanowski 中心摘要/摘要：该 U19 中心在“建议”中追求研究重点 与阿尔茨海默病相关的痴呆症会议”。13 它特别关注解决以下问题的优先事项： 多病因痴呆主题领域中的阿尔茨海默病 (AD) 和相关痴呆 (ADRD)，Lewy 身体（LB）痴呆（LBD），包括伴有LB的痴呆（DLB）和无帕金森病（PD）和有 AD14-17 的生物学定义的新指南反映了痴呆症 (PDD) 和来自 最近的 NIA 会议“神经退行性疾病的传播性：当前科学和建议” 未来的研究”（Frosch M 等人，准备中，2018 年）。 是 AD 最常见的亚型，我们发现病理性 aSyn 的积累会导致神经元。 由于不同病理性异步菌株的错误折叠和传播形成LB而导致功能障碍和死亡 和 LN，并且 aSyn 和 AD 病理学相互作用以改变彼此的分布并有助于 为了实现这些目标，项目 I 和项目 II 相互补充，项目 III 则相互补充。 IV 通过寻求阐明 AD+aSyn/LBD 与 PD 相比的 aSyn 菌株，多系统 萎缩 (MSA) 作为对照进行研究，因为它的特征是非同步神经胶质细胞质内含物 (GCI) 由一种独特的 aSyn 菌株组成，该菌株比 LBD 或 AD+aSyn 菌株更有效 aSyn.同时，项目 III 区域 AD/LBD 神经病理学与新型单克隆抗体 使用 2X2 设计将这些数据与不同的认知困难和结构成像相关联。 对比临床 AD 表型和原发性 AD 病理学，项目 IV 对此进行了补充。 测量认知、血液和脑脊髓 (CSF) 生物标志物，包括 aSyn 以及 SNP 阵列，以 更好地理解、诊断和管理 AD/LBD 的多种临床表现，以推进 aSyn 的里程碑式发现用于护理和疾病管理。 基因（SNCA）改变导致LBD致病，并且病理性aSyn是LBD中的疾病蛋白 突触核蛋白病，除了 aSyn 菌株的细胞间传播之外，还将 aSyn 置于中心舞台 宾大 U19 中心在四个方面解决了这些关键问题。 此外，该中心还将与 NIA 合作提供生物流体、DNA/RNA、 除了 aSyn 之外，过去 20 年来从宾夕法尼亚大学 ADRD 患者收集的尸检组织和数据 通过解决不同 aSyn 菌株背后的假设。 AD+aSyn/LBD，我们将阐明AD+aSyn/LBD异质性的分子基础，同时开辟新的领域 Penn U19 中心与 NIA 合作的药物发现和生物标志物开发目标 程序。