Humanized mice for investigating human stem cell-derived microglia in Alzheimers Disease

用于研究阿尔茨海默病中人类干细胞衍生的小胶质细胞的人源化小鼠

• 批准号: 10120199
• 负责人: Michael Allen Brehm
• 金额: $ 42.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10120199
• 关键词: APP-PS1; Administrative Supplement; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Award; Beta Cell; Brain; Breeding; CSF1 gene; Characteristics; Clinical Treatment; Communities; Development; Disease; Engraftment; Etiology; Funding; Future; Gliosis; Goals; Grant; Hematopoietic stem cells; Histologic; Human; Immunodeficient Mouse; Immunologics; Individual; Inflammatory; Investigation; Lead; Link; Microglia; Modeling; Molecular; Monoclonal Antibody R24; Mus; Muscle Cells; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathologic; Pathology; Patients; Phagocytes; Phenotype; Population; Property; Protein Precursors; Reporting; Research Personnel; Research Support; Resources; Risk; Role; Sampling; Senile Plaques; Study models; Synapses; The Jackson Laboratory; Therapeutic; Therapeutic Intervention; TimeLine; Transgenic Mice; Transgenic Organisms; Transplantation; United States National Institutes of Health; Work; base; biobank; cohort; cytokine; experimental study; human stem cells; humanized mouse; immunogenicity; in vivo; induced pluripotent stem cell; macrophage; model development; mouse model; multidisciplinary; nervous system disorder; neuroinflammation; next generation; novel; pre-clinical; prevent; response; risk variant; targeted treatment; tau Proteins; therapeutic target; transcriptome sequencing

ABSTRACT Inflammatory microglia are a critical regulator of neuroinflammation and are strongly linked to Alzheimer’s Disease (AD). As microglia are now a lead target for therapeutic intervention in AD, there is a clear need to develop robust pre-clinical animal models that permit investigation of human microglia in vivo, which will enable the development of new microglia-based treatments for AD. This supplemental proposal is in response to NOT-AG-20-008. The goal of this supplemental proposal is to develop novel immunodeficient mice as a resource for the study of human microglia in AD. We have formed a multi-disciplinary team consisting of expertise in microglia and neurodegenerative diseases (Dr. Schafer) and expertise in creating, validating, and sharing new models of humanized mice with the scientific community (Drs. Shultz, Brehm, Greiner). We request supplemental funds to our ongoing R24 OD026440 project. The goal of the R24 project is to develop a resource of immunodeficient mice for the study of human stem cell-derived beta cells and muscle cells. This supplemental request will accomplish our goal of moving our analyses of human stem cells and their progeny into the setting of the brain, microglia, and AD. Human CSF1 and IL34 are cytokines required for microglial development as well as survival and support different subsets of microglia. The function and relationship of each subset to AD is not known. Our Scientific Premise is that our next generation NSG mice transplanted with human hematopoietic stem cells (HSC) will develop subpopulations of human microglia that will allow the investigation of different microglial subsets and their role in AD-related neurodegeneration. We have developed NOD-scid IL2rgnull (NSG) mice that transgenically express human CSF1 or human IL34. This will allow study of human microglia in a homeostatic state. We have also obtained a NSG-Tg(APP/PS1) strain from Dr. Howell at The Jackson Laboratory (JAX) that transgenically expresses a chimeric mouse/human precursor protein of A and develops amyloid plaques. We will create NSG-Tg(APP/PS1 hIL34) and NSG-Tg(APP/PS1 hCSF1) mice to study microglia in AD. In Aim 1, we will validate and optimize the engraftment of human microglia in human HSC- engrafted NSG-Tg(hIL34), NSG-Tg(hCSF1), and in NSG-Tg(APP/PS1) mice expressing hIL34 or hCSF1. In Aim 2, we will define human microglia localization and immunological profile and determine their phagocytic and inflammatory properties basally and in the context of neurodegeneration associated with AD. As requested in NOT-AG-20-008, as a resource for our future investigation of human microglia in AD we will develop NSG-Tg(hIL34 hCSF1) mice and cross these mice with NSG-Tg(APP/PS1) mice to allow the study of both subsets of human microglia in a single recipient in a homeostatic and in a disease state, respectively. This will provide a critical resource of much needed validated platforms for investigating human microglia and their function in AD that will be readily available to the scientific community through the JAX Biorepository.

抽象的 炎症性小胶质细胞是神经炎症的关键调节剂，与阿尔茨海默氏症密切相关 疾病（AD）。由于小胶质细胞现在是AD治疗干预的主要目标，因此显然需要 开发可靠的临床前动物模型，允许研究人类小胶质细胞体内，这将使 开发基于小胶质细胞的AD治疗方法。 该补充提案是针对NOT-AG-20-008的回应。该补充提议的目标 是开发新型免疫缺陷小鼠作为研究AD中人类小胶质细胞的资源。我们 已经组成了一个由小胶质细胞和神经退行性疾病的专业知识组成的多学科团队（博士 Schafer）和专业知识在创建，验证和共享人源性老鼠的新模型与科学 社区（Shultz博士，Brehm，Greiner）。我们向正在进行的R24 OD026440要求补充资金 项目。 R24项目的目的是开发一种免疫缺陷小鼠的资源来研究人 干细胞衍生的β细胞和肌肉细胞。这个补充要求将实现我们的目标 我们对人类干细胞的分析及其在大脑，小胶质细胞和AD的环境中的进展。 人CSF1和IL34是小胶质发育所需的细胞因子以及生存和支持 小胶质细胞的不同子集。每个子集与AD的功能和关系尚不清楚。我们的科学 前提是我们用人造血干细胞移植的下一代NSG小鼠（HSC） 将开发人类小胶质细胞的亚群，这将允许投资不同的小胶质细胞 子集及其在与广告相关的神经变性中的作用。我们已经开发了点头SCID IL2RGNULL（NSG） 翻译表达人CSF1或人IL34的小鼠。这将允许研究人类小胶质细胞 稳态状态。我们还从杰克逊（Jackson）的豪威尔（Howell）博士那里获得了NSG-TG（APP/PS1）菌株 实验室（JAX）转化为表达A的嵌合小鼠/人类前体蛋白 淀粉样斑块。我们将创建NSG-TG（APP/PS1 HIL34）和NSG-TG（APP/PS1 HCSF1）小鼠进行研究 AD中的小胶质细胞。在AIM 1中，我们将验证和优化人类HSC中人类小胶质细胞的植入 植入了NSG-TG（HIL34），NSG-TG（HCSF1），在表达HIL34或HCSF1的NSG-TG（APP/PS1）小鼠中。在 AIM 2，我们将定义人类的小胶质细胞定位和免疫学特征，并确定其吞噬细胞 基本和与AD相关的神经变性的背景下，炎症特性。 根据Not-AG-20-008中的要求，作为我们未来对人类小胶质细胞投资的资源，我们 将开发NSG-TG（HIL34 HCSF1）小鼠，并用NSG-TG（APP/PS1）小鼠跨这些小鼠，以允许研究 在稳态和疾病状态下，单个受体中人类小胶质细胞的两个子集的。 这将为研究人类小胶质细胞和 它们在AD中的功能将通过JAX Biorepositor随时可用于科学界。