Preclinical Diagnostic Imaging of Amyloid

描述（由申请人提供）：淀粉样变性是一种与越来越多的疾病相关的破坏性病理，包括我们这个时代最具社会经济影响的两种疾病，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率的一个重要原因。对于这些患者，很少有治疗选择，也没有定量的临床成像技术来全身检测疾病。因此，我们的长期目标是开发淀粉样蛋白反应肽，用于这些破坏性疾病患者的内脏淀粉样变性的临床检测和治疗。在第一次资助期间，研究表明某些肝素反应性小肽与淀粉样蛋白沉积特异性反应，但与健康组织不反应。这主要是通过使用放射性标记肽作为显像剂在具有内脏AA淀粉样蛋白的小鼠以及在脑血管中具有β淀粉样蛋白的小鼠中证实的。肽与淀粉样蛋白的结合在SPECT图像和显微放射自显像中得到证实，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结合，而不管它们是由什么前体形成的。我们将利用这些新发现来开发创新的分子显像剂和肽疗法。这项为期5年的更新提案的目标是：目标1：基于我们的先导肽p5的结构，通过生成用于内脏淀粉样变性定量检测的变体，表征和开发淀粉样反应肽。目的2：评估淀粉样蛋白靶向肽在体外和体内预防和清除内脏AA、IAPP和ApoA2c以及β源性淀粉样蛋白沉积方面的治疗潜力。目的3：研究淀粉样蛋白反应肽与β(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。这将有助于我们合理设计和优化淀粉样蛋白靶向肽和治疗肽。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检测淀粉样变小鼠的新肽。此外，我们将使用我们已经建立的一系列体外试验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。这些研究将导致改进和有效的分子成像放射性示踪剂和伴随疗法，可用于这些毁灭性疾病患者的临床翻译和评估。

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.