Therapeutic Targeting of Abnormal Conformation in Neurodegenerative Disease

神经退行性疾病异常构象的治疗靶向

基本信息

批准号：
8479443
负责人：
THOMAS M WISNIEWSKI
金额：
$ 34.96万
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：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479443
关键词：
APP-PS1 Abrus Active Immunization Address Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid Proteins Amyloidosis Animal Model Antigens Behavioral Binding Blocking Antibodies British Cellular Immunity Cerebral Amyloid Angiopathy Data Development Disease Encephalitis Frontotemporal Lobar Degenerations Genetic Transcription Human Immune Immune response Immunization Immunoglobulin Variable Region Immunotherapy Inclusion Bodies Lewy Body Disease Mediating Membrane Methods Missense Mutation Modeling Molecular Conformation Monoclonal Antibodies Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinson Disease Passive Immunization Pathology Peptides Permeability Physiological PrP PrPSc Proteins Prion Diseases Prions Production Property Proteins Protocols documentation Reporting Resistance Risk Sequence Homology Terminator Codon Testing Therapeutic Toxic effect Vascular resistance abnormally phosphorylated tau anti-PrP antibodies base conformer effective therapy extracellular fibrillogenesis immunoregulation in vitro testing in vivo mimicry mouse model novel novel strategies novel therapeutics prevent public health relevance tau Proteins tau aggregation tau mutation tau-1 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ¿-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms. None of the conformational diseases has an effective therapy; however, immunomodulation has shown great promise for both AD and prion diseases. Major problems with this approach include: the potential of toxicity from encephalitis (related to excessive cell mediated immunity), the immunological targeting of both the normal and abnormal A¿, the resistance of vascular amyloid to clearance, as well as tau related pathology not being specifically addressed. The central hypothesis of this proposal is that each of these limitations can be overcome by specific targeting of abnormal oligomer conformation and development of novel methods to prevent oligomer mediated toxicity. Our novel active immunomodulation approach uses a polymerized British amyloidosis (pABri) related peptide in a predominantly ¿-sheet, oligomeric form. We hypothesized that through "conformational mimicry" the polymerized ABri peptide could induce a conformation selective immune response that will recognize both A¿ and conformationally abnormal tau. This hypothesis is supported by preliminary data in an APP/PS1 AD mouse model. Such an immunostimulatory approach should have a reduced risk of inducing auto-immune complications as it is more specific to a pathological conformer and the immunogen has no sequence homology to any known mammalian protein/peptide. We also present preliminary data that short term treatment with monoclonal 6D11, an anti-PrP antibody, reverses behavioral deficits in an AD model APP/PS1 Tg mice. This antibody blocks the binding of A¿ oligomers to PrPC. We hypothesize that blocking the binding of A¿ oligomers and PrPC is a novel therapeutic strategy for AD. These complementary approaches will aim to both increase clearance of A¿ oligomers and specifically block their toxicity.

描述（由适用提供）：许多神经退行性疾病的特征是自蛋白的构象变化为淀粉样蛋白生成，病理构象异构体，它们具有具有高结构特性，例如高```高'' - 表含量和降解的耐药性。阿尔茨海默氏病（AD）是神经退行性蛋白质构象中最常见的疾病，其中包括弥漫性路易疾病（DLBD），帕金森氏病（PD），PRION疾病，prion疾病和额叶lobar lobar nobar nobar nobar疾病（FTLD）。最有毒的构象体是寡聚形式。构型疾病没有有效的疗法；然而，免疫调节对AD和Prion疾病都显示出巨大的希望。这种方法的主要问题包括：脑炎毒性的潜力（与过量的细胞介导的免疫his有关），正常和异常A毒性的免疫学靶向，血管淀粉样蛋白对清除的耐药性，以及与TAU相关病理学的抗性。该提议的中心假设是，这些局限性都可以通过特异性靶向异常的低聚物构象和开发新方法来克服，以防止低聚物介导的毒性。我们新型的主动免疫调节方法采用聚合化的英国淀粉样变性（PABRI）相关的肽，主要是e -表，寡聚形式。我们假设，通过“构象模仿”聚合的ABRI辣椒可以诱导构象选择性免疫响应，可以识别a。和构象异常的tau。该假设在APP/PS1 AD鼠标模型中的初步数据支持。这种免疫刺激剂方法应降低诱导自身免疫并发症的风险，因为它更特异性地对病理构象异构体，并且免疫原与任何已知的哺乳动物蛋白/肽均无序列同源性。我们还提供了初步数据，即一种抗PRP抗体单克隆6D11的短期治疗逆转行为在AD模型APP/PS1 TG小鼠中定义。该抗体阻止了A低聚物与PRPC的结合。我们假设阻止A别聚体和PRPC的结合是AD的一种新型治疗策略。这些完整的方法将旨在增加对寡聚物的清除，并特别阻止其毒性。