Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis

项目1：识别阿尔茨海默病发病机制的早期生命分子决定因素

• 批准号: 10494775
• 负责人: Stacey J Rizzo
• 金额: $ 22.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494775
• 关键词: Adolescence; Adolescent; Adult; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Anatomy; Behavioral; Biological Markers; Biological Models; Biopsy; Birth; Brain; Callithrix; Callithrix jacchus jacchus; Cells; Cerebrovascular Circulation; Clinical; Clinical Data; Cognitive; Communities; Data; Disease; Disease Progression; Disease model; Early Onset Alzheimer Disease; Early identification; Emotional; Evaluation; Event; Fibroblasts; Foundations; Future; Generations; Genetic; Genetic Engineering; Genetic Risk; Goals; Human; Impaired cognition; Infant; Intervention; Investigation; Knowledge; Knowledge Portal; Life; Liquid substance; Longevity; Longitudinal Studies; Magnetic Resonance Imaging; Modeling; Molecular; Molecular Profiling; Motor; Mutation; Neuroanatomy; Neurons; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Patients; Phase; Phenotype; Physiological; Positron-Emission Tomography; Prevention; Primates; Process; Proteome; Research; Resources; Sampling; Skin; Staging; Study models; System; Tissues; Validation; Variant; Work; aged; analytical method; case control; cytokine; design; differential expression; disease diagnosis; effective therapy; healthy aging; infancy; multimodality; multiple omics; mutant; neurodevelopment; neuroinflammation; neuropathology; novel; potential biomarker; pre-clinical; presenilin-1; prevent; relating to nervous system; risk variant; social; targeted treatment; tau Proteins; tau-1; transcriptome; translational approach

PROJECT SUMMARY PROJECT 1 The overarching aims of this proposal are to identify the initial cascade of events that drive the inception and progression of Alzheimer’s Disease (AD). There is an urgent need to prevent, and treat AD. We hypothesize that genetic risk for AD confers disease pathogenesis in early life that will be detected by studying molecular and cellular events before the age of adolescence which will inform prevention. By employing a model system that more faithfully recapitulates the genetic, molecular, cellular, physiological, anatomical and structural organization of the primate brain, we will be able to identify underlying drivers of AD and better model disease pathogenesis and progression in order to prevent disease. In support of these goals, this project (Project 1) aims to identify the early life primate-specific molecular determinants of Alzheimer’s disease emergence and progression using marmosets genetically engineered with the presenilin 1 (PSEN1) risk variant, an early onset AD mutation. The PSEN1 marmoset models provide the ability to evaluate divergent changes at the molecular, cellular, and systems level from birth through infancy, adolescence, and aging. The Specific Aims of this project are: 1) to evaluate the disease trajectory of PSEN1 mutant marmosets relative to healthy age-matched and normal aged controls using established and emerging AD biomarkers; 2) to conduct comprehensive behavioral characterization of the PSEN1 marmoset models relative to healthy controls via longitudinal multimodal phenotypic characterization from neurodevelopment through lifespan; and 3) investigate the molecular signatures of neuronal cells derived from fibroblasts as a surrogate to brain. Through these specific aims, we expect to have comprehensively characterized the first genetically engineered marmoset models of AD that recapitulates the spectrum of AD-related phenotypes observed in AD patients for behavioral, cognitive, biomarker, and neuropathological hallmarks using translational approaches; identified early molecular changes at the cellular level using multi-omics approaches prior to the emergence of frank AD neuropathology and cognitive decline; and created the foundation of knowledge for the utility of genetically engineered marmosets with AD risk variants as validated models.

项目1 本提案的总体目标是确定推动启动的初始级联事件， 阿尔茨海默病（AD）的进展。迫切需要预防和治疗AD。我们假设 AD的遗传风险赋予了早期生命中的疾病发病机制，这将通过研究分子和 青春期之前的细胞事件，这将有助于预防。通过采用模型系统， 更忠实地概括了遗传、分子、细胞、生理、解剖和结构组织 我们将能够识别AD的潜在驱动因素，并更好地模拟疾病的发病机制。 和疾病的发展来预防疾病。为了支持这些目标，本项目（项目1）旨在确定 阿尔茨海默病出现和进展的早期灵长类特异性分子决定因素 用早老素1（PSEN 1）风险变体（一种早发性AD突变）进行基因工程改造的绒猴。的 PSEN 1绒猴模型提供了评估分子、细胞和免疫组织化学上的不同变化的能力。 系统水平从出生到婴儿期、青春期和衰老。该项目的具体目标是：1） 评估PSEN 1突变绒猴相对于健康年龄匹配和正常年龄的疾病轨迹 使用已建立和新出现的AD生物标志物进行对照; 2）进行全面的行为学研究， 通过纵向多模态表征PSEN 1绒猴模型相对于健康对照的特征 从神经发育到生命周期的表型表征;以及3）研究 来源于成纤维细胞的神经元细胞作为脑的替代物的特征。通过这些具体目标，我们 希望能够全面表征第一个AD的基因工程绒猴模型， 概括了在AD患者中观察到的AD相关表型的行为、认知、 生物标志物和使用翻译方法的神经病理学标志;确定的早期分子变化 在细胞水平上使用多组学方法在坦率的AD神经病理学出现之前， 认知能力下降;并为基因工程绒猴的实用性创造了知识基础 AD风险变量作为验证模型。