Validating pig models for Alzheimer's disease

项目摘要/摘要 这项提议的广泛目标是描述和建立阿尔茨海默病(AD)的猪模型。这个 具体目的是在包括APP、PSEN1和5xFAD在内的三个猪AD模型中收集新的验证数据 缺乏内源性APP和PSEN1的猪。利用我们的专业知识，猪模型将得到验证，以反映 疾病的细胞、分子和行为方面。AD是痴呆症和情感障碍的主要原因 据估计，美国人口中有620万人，但仍然需要开发有效的治疗方法。 AD的啮齿动物模型提供了关于这一潜在病理生理学的关键信息 无序。然而，这些模型不能捕捉人体生理和临床药物剂量的许多方面。 不能在较小的动物身上检测到。因此，需要AD的大型动物模型来促进我们的 了解这种疾病，并加快药物发现工作。猪很容易买到，而且是 被认为是一种优秀的生物医学模型，因为它与人类有许多相似之处，包括 心血管、肺脏、免疫、内分泌和代谢系统。此外，与啮齿动物相比， 与人类相比，模型猪更大，寿命更长，大脑结构更相似。 重要的是，猪可以执行复杂的认知任务，使它们成为AD的理想大型动物模型，这 是由记忆能力的大幅下降定义的。目前，还没有大型动物模型可以 准确反映美国阿尔茨海默氏症的症状。以解决这一重大差距 菲尔德，我们将验证美国可用的第一个AD猪模型。多样化的动物模型代表 人类阿尔茨海默病对于开发治疗方法以提高阿尔茨海默病患者的寿命和生活质量具有不可估量的价值。至 为了实现这一目标，我们组建了一个跨学科的研究团队，其中包括国家 密苏里大学猪资源与研究中心(NSRRC)和猪神经科学 佛罗里达国际大学的设施(PNF)，拥有开发和表征所需的所有专业知识 这些猪AD模型。在目标1中，我们将描述我们的APP PSEN1的基因组和生物学过程 以及5xFAD猪AD模型，以帮助将它们建立为生物医学界的新资源。在《目标2》中我们将 通过进行脑区特异性组织学检查，进一步验证AD猪模型在AD研究中的应用 评估和神经认知评估。因此，我们希望在这些猪模型中证实AD的表型 在分子、生物化学和认知水平上。总的来说，这项提议将导致收集关键数据 这是评估这些新的AD猪模型的有效性所必需的，这可以作为一种新的资源 并有助于促进我们对这种主要疾病的理解和潜在的治疗 神经退行性疾病。

Project Summary/Abstract The broad goal of this proposal is to characterize and establish pig models of Alzheimer’s disease (AD). The specific purpose is to collect novel validation data in three pig AD models including APP, PSEN1, and 5xFAD pigs lacking their endogenous APP and PSEN1. Using our expertise, the pig models will be validated to reflect cellular, molecular, and behavior aspect of the disease. AD is the leading cause of dementia and affects estimated 6.2 million people in the U.S. population, yet there remains need to develop effective treatments. Rodent models of AD have provided critical information regarding the underlying pathophysiology of this disorder. However, these models cannot capture many aspects of the human physiology, and clinical drug doses cannot be examined in smaller animals. Large animal models of AD are thus needed to facilitate our understanding of this disorder and accelerate drug discovery efforts. Pigs are readily available and are considered to be an excellent biomedical model due to numerous similarities to humans, including cardiovascular, pulmonary, immune, endocrine and metabolic systems. Additionally, in comparison to rodent models, pigs are larger, have longer lifespans and a more similar brain structure compared to humans. Importantly, pigs can perform complicated cognitive tasks making them an ideal large animal model of AD, which is defined by a substantial decline in memory capabilities. Currently, there are no large animal models that accurately reflect the symptoms of Alzheimer’s disease in the U.S. To address this significant gap in the field, we will validate the first pig models of AD available in the U.S. Diversifying animal models representing human AD will be invaluable for developing therapeutics to improve the longevity and quality of life in AD. To achieve this goal, we have assembled an interdisciplinary research team including members of the National Swine Resource and Research Center (NSRRC) at the University of Missouri and the Porcine Neuroscience Facility (PNF) at Florida International University that has all the necessary expertise to develop and characterize these pig AD models. In Aim 1 we will characterize the genome and biological processes of our APP, PSEN1 and 5xFAD pig AD models to help establish them as a novel resource to biomedical community. In Aim 2 we will further validate the AD pig models for their use in AD research by performing brain region-specific histological evaluations and neurocognitive assessments. Thus, we expect to confirm phenocopies of AD in these pig models at molecular, biochemical, and cognitive levels. Collectively, this proposal will result in collection of critical data that is needed to assess the validity of these new pig models for AD, which can serve as a novel resource to the biomedical community and help advance our understanding and potential treatments of this major neurodegenerative disorder.