Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease

了解发病机制和治疗阿尔茨海默病的新方法

基本信息

批准号：
10621825
负责人：
THOMAS M WISNIEWSKI
金额：
$ 235.85万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621825
关键词：
Acceleration Address Advisory Committees Affect Age of Onset Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid Amyloid beta-Protein Animal Model Animals Apolipoprotein E Apolipoproteins Area Automobile Driving Awareness Behavior Behavior assessment Behavioral Binding Bioinformatics Biological Markers Biometry Biostatistical Methods Blood Vessels Cerebral Amyloid Angiopathy Clinical Collaborations Communities Complex Consensus Coupling Data Data Analyses Databases Deposition Development Disease Progression Education Ensure Experimental Designs Genotype Goals Hemorrhage Image Immunology Immunotherapy Interdisciplinary Study Label Late Onset Alzheimer Disease Magnetic Resonance Imaging Methodology Methods Mitochondria Molecular Conformation Pathogenesis Pathology Peptoids Pharmaceutical Chemistry Play Progress Reports Protein Conformation Protein Isoforms Proteins Proteome Proteomics Recording of previous events Research Research Personnel Rodent Model Role Safety Sampling Senile Plaques Synaptic plasticity Techniques Technology Testing Therapeutic Transgenic Mice Transgenic Organisms United States National Institutes of Health Work abeta deposition abeta oligomer aged amyloid pathology apolipoprotein E-3 apolipoprotein E-4 brain parenchyma clinically relevant data management data sharing genetic risk factor glucose metabolism human data human tissue immunoregulation innovation insight laser capture microdissection meetings microPET mouse model neuroimaging neuropathology novel novel strategies novel therapeutics operation power analysis programs protein oligomer response side effect small molecule synergism tau Proteins therapeutic development therapeutically effective therapy outcome treatment response

项目摘要

OVERALL PROGRAM SUMMARY/ABSTRACT In this P01 proposal entitled: “Novel Approaches to Understand the Pathogenesis and Treat Alzheimer’s Disease”, we seek to gain a better understanding of the heterogeneous pathogenesis of AD and how it is influenced by apolipoprotein (apo) E isotypes. The apoE4 allele is the major genetic risk factor for late-onset AD and has been strongly associated with increased amyloid plaques deposition in brain parenchyma and advanced vascular amyloid pathology; as well as, enhanced Aβ oligomerization. ApoE is also involved in synaptic plasticity, glucose metabolism, mitochondrial function, and vascular integrity. Currently, there is no consensus on how different apoE genotypes contribute to the pathogenesis of AD. The interrelated studies proposed in the three projects of this P01 will help elucidate this complex role of apoE in AD. Hence this P01 is addressing an issue of great significance. We propose an integrated, multidisciplinary research endeavor that brings together investigators with an extensive history of successful collaboration, who have expertise in diverse areas including proteomics, bioinformatics, neuropathology, AD mouse models, immunology, µMRI, µPET, medicinal chemistry and biomarker studies. Across all projects we will apply our innovative proteomic methods (with the assistance of the proteomics/neuropathology Core B) and use of common AD models and behavioral assessments (with the assistance of the transgenic/behavioral Core C), along with state-of-the-art biomarker technology using SIMOA and P01 investigator developed µMRI methodologies, to ensure synergism across all P01 studies. Scientific rigor of the P01 will be ensure by the Biostatistics and Bioinformatics Core (Core D). The three projects of this P01 are focused on the differential role apolipoprotein E (apoE) isoforms play in: 1) AD plaque and vessel amyloid development as assessed by unbiased proteomics across the full spectrum of AD pathology (Project 1); 2) innovative therapeutic approaches that target the Aβ/apoE interaction (Project 2); and 3) responses to our novel therapeutic immunomodulation that targets abnormal conformation (Project 3). Combined our efforts are anticipated to enhance our understanding of the differential effects of apoE isotypes on AD pathogenesis and accelerate the discovery of effective therapeutic approaches that address these diverse roles.

总体程序摘要/摘要在这个P01的建议中，题为：“了解发病机理并治疗阿尔茨海默氏症的新方法疾病”，我们寻求更好地了解AD的异质发病机理受载脂蛋白（APO）E同种型的影响。 APOE4等位基因是晚期的主要遗传危险因素 AD，并且与大脑实质中淀粉样蛋白斑块沉积的增加密切相关晚期血管淀粉样病理学；以及增强的Aβ寡聚化。 Apoe也参与了突触可塑性，葡萄糖代谢，线粒体功能和血管完整性。目前，没有关于不同的APOE基因型如何有助于AD的发病机理的共识。相互关联的研究在本P01的三个项目中提出的建议将有助于阐明APOE在AD中的复杂作用。因此，这个P01是解决一个重要意义的问题。我们提出了一项综合的，多学科的研究努力，汇集了与成功合作的广泛历史的调查员，他们有专家潜水区域，包括蛋白质组学，生物信息学，神经病理学，AD小鼠模型，免疫学，µMRI，µMRI， µPET，医学化学和生物标志物研究。在所有项目中，我们将应用我们的创新蛋白质组学方法（在蛋白质组学/神经病理学核心的帮助下），并使用常见的AD模型和行为评估（在转基因/行为核心C的帮助下），以及最新的使用SIMOA和P01研究者开发了µMRI方法的生物标志物技术，以确保协同作用在所有P01研究中。 P01的科学严谨性将由生物统计学和生物信息学核心确保（核心D）。该P01的三个项目集中在鉴别作用载脂蛋白E（APOE）同工型上在以下 AD病理学频谱（项目1）； 2）针对Aβ/APOE相互作用的创新治疗方法（项目2）; 3）对靶向异常构象的新型治疗免疫调节的反应（项目3）。预计我们的努力将增强我们对 APOE同种型在AD发病机理上，并加速了有效的治疗方法的发现解决这些潜水员的角色。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Life stressors significantly impact long-term outcomes and post-acute symptoms 12-months after COVID-19 hospitalization.

DOI：
10.1016/j.jns.2022.120487
发表时间：
2022-12-15
期刊：
JOURNAL OF THE NEUROLOGICAL SCIENCES
影响因子：
4.4
作者：
Frontera, Jennifer A.;Sabadia, Sakinah;Yang, Dixon;de Havenon, Adam;Yaghi, Shadi;Lewis, Ariane;Lord, Aaron S.;Melmed, Kara;Thawani, Sujata;Balcer, Laura J.;Wisniewski, Thomas;Galetta, Steven L.
通讯作者：
Galetta, Steven L.

High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer's disease associated with chronic platelet activation.

高脂肪饮食诱导的动脉粥样硬化会促进与慢性血小板活化相关的阿尔茨海默病三重转基因 (3 × Tg) 小鼠模型中的神经变性

DOI：
10.1186/s13195-021-00890-9
发表时间：
2021-08-28
期刊：
Alzheimer's research & therapy
影响因子：
0
作者：
Wang M;Lv J;Huang X;Wisniewski T;Zhang W
通讯作者：
Zhang W

ADAMTS18 Deficiency Affects Neuronal Morphogenesis and Reduces the Levels of Depression-like Behaviors in Mice.

ADAMTS18 缺乏会影响小鼠神经元形态发生并降低抑郁样行为水平

DOI：
10.1016/j.neuroscience.2018.12.025
发表时间：
2019-02-10
期刊：
Neuroscience
影响因子：
3.3
作者：
Zhu R;Pan YH;Sun L;Zhang T;Wang C;Ye S;Yang N;Lu T;Wisniewski T;Dang S;Zhang W
通讯作者：
Zhang W

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia.