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Protein variants as blood based biomarkers for diagnosing and staging AD

蛋白质变体作为血液生物标志物用于 AD 诊断和分期

基本信息

批准号：
9977069
负责人：
MICHAEL R SIERKS
金额：
$ 34.96万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977069
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-Protein Amyotrophic Lateral Sclerosis Antibodies Aphasia Apraxias Ataxia Binding Biological Assay Biological Markers Blood specimen Brain Cellular Stress Clinical Clinical assessments Cognitive Cohort Studies Collection Confusion DNA-Binding Proteins Diagnosis Diagnostic Disease Disease Outcome Disease Progression Early Diagnosis Effectiveness Environmental Risk Factor Fingerprint Freezing Frontotemporal Dementia Generations Goals Human Immunoglobulin Fragments Individual Injury Length Lewy Body Dementia Link Memory Monitor Morphology Neurodegenerative Disorders Neurons Parkinson Disease Parkinsonian Disorders Patient-Focused Outcomes Patients Performance Plasma Play Population Proteins Protocols documentation Publications Reaction Reagent Research Risk Factors Role Sampling Side Staging Stress Symptoms Tars Therapeutic Time Toxic Environmental Substances Variant Visual Hallucination alpha synuclein base blood-based biomarker cortical visual impairment cost direct application disorder control economic cost effective therapy imaging agent in vivo individual patient nanobodies new technology personalized diagnostics personalized therapeutic protein aggregation radiotracer success tau Proteins therapeutic target tool

项目摘要

ABSTRACT There are over 5 million cases of Alzheimer's Disease (AD) in the US, the number of cases is expected to nearly double over the next 15 years, and the total annual economic costs are over $225 billion. Despite these tremendous costs, there is still no effective treatment for AD. The protein amyloid-beta (Aß) has been linked to AD for many years, but despite thousands of publications on the connection between Aß and AD, there is still much confusion over the role of Aß in AD, and therapeutics targeting Aß have met with very limited success. The protein tau has also been linked to AD. Similar to Aß, tau also exists in a wide variety of different forms in the human brain, so the role of tau in the onset and progression of AD is also not clear. Two other neuronal proteins, alpha-synuclein (a-syn) and Tar-DNA binding protein (TDP-43), have also been implicated in neurodegenerative diseases and play major roles in Parkinson's disease and Amyotrophic lateral sclerosis (ALS), respectively. All four of these key neuronal proteins, Aß, tau, a-syn and TDP-43, are prone to misfolding and aggregation and small toxic aggregates of each of these proteins are thought to play a role in the onset, progression and spread of a number of different neurodegenerative diseases. Cellular stress caused by toxic aggregates of one protein can induce formation of toxic aggregates of other proteins ultimately resulting in a spectrum of neurodegenerative diseases. Clearly generation and accumulation of toxic protein variants of tau, Aß, TDP-43 and a-syn AD play an important role in the onset and progression of neurodegenerative diseases including AD. Because of the important role of these protein variants in different neurodegenerative disease, we hypothesize that there are distinct toxic protein variant profiles that distinguish AD, and that levels of key protein variants in these profiles will change during progression of AD and also from patient to patient. We hypothesize that by determining each individual's toxic protein variant fingerprint using biomarkers present in sera or plasma samples, we can facilitate pre-symptomatic diagnosis and staging of AD, identify appropriate therapeutic strategies for each individual patient, and also monitor effectiveness of different therapeutics in real time. The goal of this proposal is to identify blood based biomarker fingerprints that distinguish different stages AD, including presymptomatic AD, and that identify the most appropriate therapeutic strategy for each individual patient. We developed novel technology that enables us to generate antibody fragments (nanobodies) that selectively bind disease related protein variants. We have a panel of 15 nanobodies to different toxic variants of Aß, tau, a-syn and TDP-43 and have shown that we can detect these variants in blood samples of patients suffering from AD, PD and other neurodegenerative diseases, but not in age-matched cognitively normal cases. The aims of this proposal are to utilize our panel of nanobodies that selectively recognize different disease related forms of Aß, tau, a-syn and TDP-43 to characterize a set of longitudinal plasma samples taken from AD and age-matched control patients. These studies will define protein variant fingerprints that not only distinguish AD from cognitively normal controls, but will define different fingerprints for different stages of AD. We will then characterize a larger set of samples from a clinical population to determine protein variant fingerprints that correlate with different clinical symptoms, such as parkinsonism, aphasia and ataxia. Defining the various protein variant fingerprints associated with different stages and clinical manifestations of AD will provide a very powerful tool to facilitate presymptomatic and personalized diagnoses of AD, indicate the most appropriate therapeutic strategy for each individual patient, and provide a means to monitor the effectiveness of the selected therapeutic in real time.

摘要在美国有超过500万例阿尔茨海默病（AD）病例，预计病例数将达到1000万。在今后15年中几乎翻一番，每年的经济损失总额超过2 250亿美元。尽管有这些尽管花费巨大，但仍然没有有效的治疗AD的方法。淀粉样蛋白β（AAPs）与 AD多年来，但尽管有成千上万的出版物对之间的联系，但仍然有关于Ablation在AD中的作用存在许多困惑，靶向Ablation的治疗方法的成功非常有限。 tau蛋白也与AD有关。类似于Tau，tau也以各种不同的形式存在于细胞中。因此，tau蛋白在AD发病和进展中的作用也不清楚。两个神经元 α-突触核蛋白（α-syn）和Tar-DNA结合蛋白（TDP-43）也与神经退行性疾病，并在帕金森病和肌萎缩侧索硬化症中发挥主要作用 (ALS)，分别。所有这四种关键的神经元蛋白质，Asia 3，tau，a-syn和TDP-43，都容易发生错误折叠，并且这些蛋白质中的每一种的聚集和小的毒性聚集被认为在发病中起作用，许多不同的神经退行性疾病的进展和传播。有毒物质引起的细胞应激一种蛋白质的聚集体可诱导其他蛋白质的毒性聚集体的形成，最终导致神经退行性疾病谱。很明显，tau蛋白的毒性蛋白变体的产生和积累， ADP、TDP-43和a-syn AD在神经退行性疾病的发生和发展中起重要作用包括AD。由于这些蛋白质变体在不同的神经退行性疾病中的重要作用，疾病，我们假设有不同的毒性蛋白质变体谱，区分AD，这些谱中的关键蛋白质变体的水平将在AD的进展过程中发生变化，病人对病人我们假设通过测定每个个体的毒性蛋白变体使用血清或血浆样本中存在的生物标志物进行指纹识别，我们可以促进症状前 AD的诊断和分期，为每位患者确定适当的治疗策略，以及还可以真实的实时监测不同疗法的有效性。本提案的目的是确定基于血液的生物标志物指纹可区分不同阶段的AD，包括症状前AD，并为每个患者确定最合适的治疗策略。我们开发新技术使我们能够产生选择性结合疾病的抗体片段（纳米抗体）相关蛋白质变体。我们有一组15种针对不同毒性变体的纳米抗体，包括A12，tau，a-syn和 TDP-43，并且已经表明我们可以在患有AD、PD和其他疾病的患者的血液样品中检测到这些变体。和其他神经退行性疾病，但不是在年龄匹配的认知正常的情况下。这项提议的目的是利用我们的纳米抗体小组，选择性地识别不同的疾病相关形式的Δ β、tau、a-syn和TDP-43来表征一组纵向血浆样品 AD和年龄匹配的对照患者。这些研究将定义蛋白质变体指纹，这将有助于区分AD与认知正常对照，但将为AD的不同阶段定义不同的指纹。然后，我们将表征来自临床人群的较大样本集，以确定蛋白质变体指纹与不同的临床症状相关，如帕金森症，失语症和共济失调。限定与AD的不同阶段和临床表现相关的各种蛋白质变体指纹将提供了一个非常强大的工具，以促进症状前和个性化诊断的AD，表明最为每位患者提供适当的治疗策略，并提供监测有效性的方法所选治疗剂的真实的时间。