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

基本信息

批准号：
10654792
负责人：
VIRGINIA M LEE
金额：
$ 362.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654792
关键词：
Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Archives Area Autopsy Bioinformatics Biological Biological Markers Biological Models Biometry Blood Caring Cells Clinical Cognition Cognitive Collaborations Complement Cytoplasmic Inclusion DNA Data Data Correlations Dementia Dementia with Lewy Bodies Diagnosis Disease Disease Management Genetic Goals Guidelines Heterogeneity 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 Neurodegenerative Disorders Neuronal Dysfunction Parkinson Disease Parkinson&apos s Dementia Pathogenicity Pathologic Pathology Patients Pennsylvania Preparation Principal Investigator Proteins Qualifying RNA Recommendation Research Personnel Research Priority SNP array Science Technology Tissues Universities Vision Work alpha synuclein behavioral impairment biomarker development biomarker panel data management design disease heterogeneity disease phenotype drug discovery in vivo medical schools meetings mixed dementia neuron loss neuropathology new therapeutic target novel novel therapeutics precision medicine programs progressive neurodegeneration structural imaging symposium synucleinopathy transmission process

项目摘要

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.

美国国家老化研究所（NIA）Penn U19“阿尔茨海默氏病和相关痴呆症”。首席研究员：John Q. Trojanowski 中心摘要/摘要：这个U19中心在“建议的建议中攻击研究重点阿尔茨海默氏病与疾病相关的痴呆症会议”。13它尤其着重于针对解决的优先事项阿尔茨海默氏病（AD）和相关痴呆症（ADRD）在多个病因痴呆症的主题领域，路易身体（LB）痴呆症（LBD），包括具有LBS（DLB）和帕金森氏病的痴呆，没有（PD）痴呆症（PDD），《 AD14-17生物学定义的新指南》，反映了来自最近关于“神经退行性疾病传播性的NIA会议：当前的科学和建议为了将来的研究”（Frosch M等人，《准备》，2018年）。在ADRD中，广告具有丰富的LB共同病理学是AD最常见的亚型。我们假设病理ASYN的积累导致神经元功能障碍和死亡由于不同病理ASYN的折叠和传播而导致的死亡，形成LBS 和LNS以及Asyn和Ad病理学相互作用以修改彼此的分布并有助于行为障碍。为了实现这些目标，项目I和II相互补充并项目III 与PD相比萎缩（MSA）是对照研究的，因为它的特征是Asyn胶质细胞质内包含（GCIS）与LBD或AD+ASYN菌株更有潜力的不同ASYN菌株完成 Asyn。同时，Project III用新型的单克隆抗体分析区域AD/LBD神经病理学（mab）将这些数据与潜水员认知难度和结构成像相关联。使用2x2设计这与临床AD表型和原发性AD病理形成对比。这是由项目IV完成的测量认知，血液和脑脊（CSF）生物标志物，包括Asyn以及SNP阵列更好地理解，诊断和管理AD/LBD的潜水员临床表现采用精确的医学方法进行护理和疾病管理。阿森的里程碑发现基因（SNCA）改变LBD的致病性，该病理ASYN是疾病蛋白突触核酸，除了ASYN菌株的细胞间扩散外，Asyn位于中心阶段了解AD+ASYN和LBD的机制。这个Penn U19中心解决了四个关键问题由四个核心支持的项目。此外，该中心还将与NIA一起提供生物流体，DNA/RNA，除Asyn外，在过去20年中，在过去20年中从ADRD患者收集的尸检组织和数据合格的调查员的压力。通过解决以下假设：独特的Asyn菌株是基础的 AD+ASYN/LBD，我们将阐明AD+ASYN/LBD中异质性的分子基础与NIA合作的Penn U19中心的药物发现和生物标志物开发目标程序。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lewy Body Dementia Association's Industry Advisory Council: proceedings of the second annual meeting.

DOI：
10.1186/s13195-021-00868-7
发表时间：
2021-07-08
期刊：
Alzheimer's research & therapy
影响因子：
0
作者：
Goldman JG;Boeve BF;Armstrong MJ;Galasko DR;Galvin JE;Irwin DJ;Leverenz JB;Marder K;Abler V;Biglan K;Irizarry MC;Keller B;Lai R;Munsie L;Belleville M;Chaney O;Richard I;Taylor A;Graham T
通讯作者：
Graham T

The neuropsychiatry of Parkinson's disease: advances and challenges.

DOI：
10.1016/s1474-4422(21)00330-6
发表时间：
2022-01
期刊：
The Lancet. Neurology
影响因子：
0
作者：
Weintraub D;Aarsland D;Chaudhuri KR;Dobkin RD;Leentjens AF;Rodriguez-Violante M;Schrag A
通讯作者：
Schrag A

Movement in Aesthetic Experiences: What We Can Learn from Parkinson Disease.