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）：淀粉样变性是一种破坏性病理，与越来越多的疾病相关，包括当今时代对社会经济影响最大的两种疾病：阿尔茨海默病（Abeta 淀粉样蛋白）和 2 型糖尿病（IAPP 淀粉样蛋白）。此外，70 岁以上人群和非裔美国男性的心脏淀粉样变性现在被认为是发病的重要原因。对于这些患者来说，治疗选择很少，也没有用于全身疾病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，用于临床检测和治疗患有这些破坏性疾病的患者的内脏淀粉样变性。 在第一个资助期间，研究表明某些肝素反应性小肽会与淀粉样沉积物发生特异性反应，但不会与健康组织发生反应。这主要是通过使用放射性标记的肽作为显像剂在内脏 AA 淀粉样蛋白的小鼠以及脑血管系统中具有 Abeta 淀粉样蛋白的小鼠中得到证实的。肽与淀粉样蛋白的结合在 SPECT 图像和显微放射自显影照片中得到证实，并通过组织生物分布测量进行量化。最近的数据表明，这些肽不仅与所有淀粉样沉积物中存在的高电荷糖胺聚糖结合，而且与蛋白原纤维本身结合，无论它们形成的前体如何。 我们将利用这些新发现来开发创新的分子成像剂和肽疗法。这个 5 年更新提案的目标是： 目标 1：基于我们的先导肽 p5 的结构，通过生成用于定量检测内脏淀粉样变性的变体来表征和开发淀粉样蛋白反应性肽。目标 2：评估淀粉样蛋白靶向肽在体外和体内预防和去除内脏 AA、IAPP 和 ApoA2c 以及 Abeta 衍生的淀粉样蛋白沉积物的治疗潜力。目标 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 原纤维提取物结合的基本过程。这将增强我们对淀粉样蛋白靶向和治疗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、显微放射自显影和生物分布测量来测试患有淀粉样变性的小鼠中的新肽。此外，我们将使用我们已经建立的一系列体外测定来测量肽的治疗潜力，并研究控制这些试剂与淀粉样蛋白相互作用的基本过程。这些研究将带来改进和有效的分子成像放射性示踪剂和伴随疗法，这些疗法可以在患有这些毁灭性疾病的患者中进行临床转化和评估。