Preclinical Diagnostic Imaging of Amyloid

淀粉样蛋白的临床前诊断成像

• 批准号: 8729574
• 负责人: JONATHAN S WALL
• 金额: $ 39.52万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729574
• 关键词: African American; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animals; Attention; Autoradiography; Binding; Biodistribution; Brain; Cardiac; Cerebrum; Charge; Chronic Disease; Clinical; Clinical Trials; Companions; Data; Deposition; Detection; Diagnosis; Diagnostic Imaging; Disease; Electrostatics; Evaluation; Funding; Glycosaminoglycans; Goals; Grant; Heart; Heparan Sulfate Proteoglycan; Heparin; Heparin Binding; Image; Imaging Techniques; In Vitro; Inflammation; Kidney; Label; Laboratories; Lead; Measurement; Measures; Methods; Mind; Monitor; Morbidity - disease rate; Multiple Myeloma; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Pathology; Patients; Peptides; Performance; Peripheral; Photons; Plasma Cells; Positron-Emission Tomography; Process; Protein Precursors; Proteins; Reagent; Series; Site; Structure; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tracer; Translating; Variant; Visceral; X-Ray Computed Tomography; amyloid formation; amyloid imaging; amyloidogenic apolipoprotein A-II; base; design; fibrillogenesis; improved; in vitro Assay; in vivo; innovation; men; molecular imaging; mortality; non-invasive imaging; novel; physical property; pre-clinical; prevent; protein aminoacid sequence; public health relevance; radiotracer; response; single photon emission computed tomography; therapeutic target; tomography; treatment planning

DESCRIPTION (provided by applicant): Amyloidosis is a devastating pathology associated with a growing number of diseases, including two of the most socio-economically impacting conditions of our time, Alzheimer's disease (Abeta amyloid) and type 2 diabetes (IAPP amyloid). Furthermore, cardiac amyloidosis in people over the age of 70 and in African American men is now recognized as a significant cause of morbidity. For these patients, there are few treatment options and no quantitative clinical imaging techniques for whole body detection of disease. Therefore, our long term goals are to develop amyloid-reactive peptides for the clinical detection and therapy of visceral amyloidosis in patients with these devastating conditions. During the first grant period it was shown that certain heparin-reactive small peptides specifically reacted with amyloid deposits but not with healthy tissues. This was demonstrated principally by using radioactively labeled peptides as imaging agents in mice with visceral AA amyloid as well as in mice with Abeta amyloid in the brain vasculature. Binding of peptides with amyloid was evidenced in SPECT images and micro-autoradiographs and was quantified by tissue biodistribution measurements. Recent data has now indicated that these peptides bind not only with highly-charged glycosaminoglycans that are present in all amyloid deposits but also the protein fibrils themselves, regardless of the precursor from which they are formed. We will leverage these novel findings to develop innovative molecular imaging agents and peptide therapeutics. The aims of this 5 year renewal proposal are to: Aim 1: Characterize and develop amyloid-reactive peptides, based on the structure of our lead peptide, p5, by generating variants for the quantitative detection of visceral amyloidosis. Aim 2: Evaluate the therapeutic potential o amyloid-targeting peptides in vitro and in vivo for preventing and removing visceral AA, IAPP, and ApoA2c as well as Abeta-derived amyloid deposits. Aim 3: Examine the fundamental processes underlying the binding of amyloid-reactive peptides with Abeta (1-40) and IAPP synthetic fibrils, as well as AA and ApoA2c fibril extracts. This will enhance our rational design and optimization of amyloid-targeting and therapeutic peptides. To achieve these goals we will combine advanced small animal SPECT/CT imaging, micro- autoradiography and biodistribution measurements for testing new peptides in mice with amyloidosis. Additionally, we will use a battery of in vitro assays that we have established to measure the therapeutic potential of the peptides and investigate the fundamental processes governing the interactions of these reagents with amyloid. These studies will lead to improved and effective molecular imaging radiotracers and companion therapeutics that can be translated and evaluated clinically in patients with these devastating diseases.

描述（由申请人提供）：淀粉样变性是与越来越多的疾病相关的毁灭性病理，包括我们时代中社会经济影响最大的两个疾病，阿尔茨海默氏病（ABETA淀粉样蛋白）和2型糖尿病（IAPP淀粉样蛋白）。此外，现年70岁以上和非洲裔美国男性的人的心脏淀粉样变性现在被认为是发病率的重要原因。对于这些患者，几乎没有治疗选择，并且没有用于疾病全身检测的定量临床成像技术。因此，我们的长期目标是开发淀粉样蛋白反应性肽，用于患有这些毁灭性疾病的患者内脏淀粉样变性的临床检测和治疗。 在第一个赠款期间，表明某些肝素反应性小肽与淀粉样蛋白沉积物专门反应，但与健康组织不反应。这主要通过在具有内脏AA淀粉样蛋白的小鼠以及在脑脉管系统中具有ABETA淀粉样蛋白的小鼠中使用放射性标记的肽作为成像剂作为成像剂。肽与淀粉样蛋白的结合在SPECT图像和微型运动仪中得到了证明，并通过组织生物分布测量进行了定量。最近的数据现在表明，这些肽不仅与所有淀粉样蛋白沉积物中存在的高电荷糖胺聚糖结合，而且与蛋白质原纤维本身之间的结合，无论它们形成的前体是什么。 我们将利用这些新颖的发现来开发创新的分子成像剂和肽疗法。这5年更新建议的目的是：AIM 1：根据我们的铅肽P5的结构来表征和发展淀粉样蛋白反应性肽P5，通过生成用于定量检测内脏淀粉样变性的变体。 AIM 2：在体外和体内评估淀粉样蛋白靶向肽的治疗潜力，以防止和去除内脏AA，IAPP和APOA2C以及ABETA衍生的淀粉样蛋白沉积物。 AIM 3：检查淀粉样蛋白反应性肽与ABETA（1-40）和IAPP合成原纤维以及AA和APOA2C原纤维提取物的结合的基本过程。这将增强我们对淀粉样蛋白靶向和治疗性肽的合理设计和优化。 为了实现这些目标，我们将结合先进的小动物SPECT/CT成像，显微自显影和生物分布测量，以测试与淀粉样变性的小鼠新肽的测试。此外，我们将使用一系列体外测定，我们已经确定这些测定法来测量肽的治疗潜力，并研究管理这些试剂与淀粉样蛋白相互作用的基本过程。这些研究将导致改善和有效的分子成像放射性示例和伴侣疗法，这些疗法可以在这些毁灭性疾病的患者中进行临床进行翻译和评估。