New Molecular Signatures in Alzheimer's Disease

阿尔茨海默病的新分子特征

基本信息

批准号：
9317757
负责人：
ERKKI RUOSLAHTI
金额：
$ 29.25万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317757
关键词：
Affinity Chromatography Alpha Cell Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Precursor Animal Model Antibodies Area Astrocytes Bacteriophages Binding Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases CD69 antigen Cell Differentiation process Cells Code Data Development Diagnostic Disease Endothelial Cells Growth Factor Hippocampus (Brain)Homing Human Huntington Disease Individual Lead Lesion Lesion by Stage Libraries Mass Spectrum Analysis Methods Molecular Molecular Biology Techniques Molecular Profiling Molecular Target Mus Mutation Names Neurons Parkinson Disease Pathogenesis Patients Peptide Library Peptide Receptor Peptides Phage Display Process Proteins Rest Sampling Senile Plaques Site Small Interfering RNA Specificity Structure Testing Therapeutic Tissues Transfection Transgenic Animals Transgenic Mice Validation brain tissue drug development experimental study extracellular in vivo induced pluripotent stem cell intravenous injection knock-down mouse model neurovascular unit new therapeutic target novel novel strategies receptor screening targeted treatment therapeutic target vascular abnormality

项目摘要

Project Summary Screening with in vivo phage display of constrained peptide libraries (comprising about different 108 sequences) has been employed as a new approach to identify specific molecular signatures present in the brains of transgenic mice that model Alzheimer's Disease (AD). The transgenic animal model used for this screening is the J20 tg hPPP, that encodes amyloid precursor protein with two mutations associated with human AD. Three peptides that specifically recognize the hippocampus (the primary site of the disease) in the J20 mice have been identified. These peptides accumulate from an intravenous injection in the hippocampal area of the diseased brains and not in the brains of normal littermates. The lead peptide has been shown to bind to activated astrocytes in the neurovascular unit of AD hippocampus. This peptide also recognizes human AD-derived samples: Endothelial cells differentiated from human AD iPS cells bind the peptide, whereas cells prepared similarly from a control individual do not, and the peptide also binds to brain sections from a patient with sporadic AD. This application proposes to identify the molecular targets (receptors) for these peptides. These molecules, because they distinguish AD from normal brain, may reveal new features of the pathogenesis of AD. They should also provide new opportunities for diagnostic and therapeutic targeting of AD. The approach proposed here significantly differs from the current state of the art in the field, as current approaches have generally focused on targeting misfolded or aberrant proteins such as amyloid plaques. In contrast, the first three peptides from the phage screens recognize specific changes in the vascular and extravascular neuronal tissue of AD hippocampus, and do so prior to any plaque development. !

项目摘要用体内噬菌体显示约束肽库的筛查（约为不同的108 序列）已被用作一种新方法，以识别存在于模拟阿尔茨海默氏病（AD）的转基因小鼠的大脑。用于此的转基因动物模型筛选是J20 TG HPPP，它编码具有两个突变的淀粉样前体蛋白人类广告。三种特异性识别海马（疾病的主要部位）的肽已经确定了J20小鼠。这些肽是从海马静脉注射中积聚的患病的大脑区域，而不是正常同窝窝的大脑。已显示铅肽已显示与AD海马的神经血管单元中的活化星形胶质细胞结合。这种肽也认识到人类 AD衍生的样品：与人AD IPS细胞区分开的内皮细胞结合肽，而细胞结合了细胞从对照个体中类似地制备，并且肽也与患者的脑部结合带有零星的广告。该应用建议确定这些肽的分子靶标（受体）。这些分子，因为它们将AD与正常大脑区分开，可能会揭示 AD发病机理。他们还应该为诊断和治疗定位提供新的机会广告。此处提出的方法与现场的当前最新状态有很大不同，因为方法通常集中于靶向误折或异常的蛋白质（例如淀粉样蛋白斑）。在对比，来自噬菌体筛网的前三个肽识别血管和 AD海马的血管外神经元组织，并在发生任何牙菌斑之前进行。呢