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Human Genetic Disease Modeling and Physiology Core

人类遗传疾病建模和生理学核心

基本信息

批准号：
10270091
负责人：
Alisha Marie Gruntman
金额：
$ 19.26万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270091
关键词：
Albumins Alleles Animal Model Benchmarking Biological Assay Blood Bronchoalveolar Lavage Capsid Clinical Collaborations Disadvantaged Disease Progression Disease model Dose Elastases Engraftment Enterobacteria phage P1 Cre recombinase Ferrets Genes Growth Hepatocyte Human Human Genetics Iowa Knock-in Mouse Knockout Mice Laboratories Libraries Liver LoxP-flanked allele Lung Lung diseases Modeling Mus Mutation Patients Phenotype Physiological Physiology Play Production Pulmonary function tests Residual state Rodent Role Serotyping Testing Therapeutic Therapeutic Intervention Time Transgenes Treatment Efficacy Universities Veterinary Medicine Veterinary Schools Work X-Ray Computed Tomography alpha 1-Antitrypsin Deficiency clinically relevant gene therapy genome editing humanized mouse mouse genetics mouse model novel promoter pulmonary function response screening success therapeutic evaluation

项目摘要

Core B - Project Summary To have successful therapies for Alpha-1 antitrypsin deficiency it is necessary to have animal models that recapitulate the phenotypes see in human patients to test therapeutics, including gene therapy and genome editing approaches, and develop clinically relevant therapeutic benchmarks to ascertain the success of those therapies. To that aim this Core is working with Project 1 (Flotte) to create an AAT-Null or PiZ ferret that conditionally expresses human AAT (hAAT) as well as a murine model of the PiZ mutation on the background of the AAT knock-out mouse created in our group. The knock-out mouse recapitulates a lung phenotype with its complete lack of AAT production, but does not completely model the state of the PiZ AAT patient who have some residual blood levels of AAT that produce residual anti-elastase activity. In this Core we aim to create and characterize an AAT-KO-PiZ mouse on the AAT-KO background and well as characterize an existing AAT-KO/PiZ cross mouse. In addition to being a more relevant model to test gene therapies, the AAT-KO-PiZ mouse will also serve as the model to further investigate genome editing of the Z-AAT alleles in Project 2 (Xue). The current PiZ mouse contains multiple copies of the PiZ gene, making it a non-ideal model for genome editing. Both mouse models will allow us to elucidate further the role that the PiZ mutation plays without the presence of wild-type murine AAT, something that has not been modeled in the mouse before. In Core B we will also produce humanized liver NSG-PiZ mice to select for AAV serotypes that target human hepatocytes for Project 3 (Wang). In addition to the production of mouse and ferret models for use in Projects 1, 2, and 3 we will also work with Projects 1 and 2 to characterize the pulmonary phenotype responses to gene therapy and genome editing. The core will offer novel expertise in rodent pulmonary function testing, bronchoalveolar lavage testing and facilitation of lung computed tomography in collaboration with Dr. Bankier and Tufts Cummings School of Veterinary Medicine.

核心B -项目摘要为了成功治疗α-1抗胰蛋白酶缺乏症，有必要使动物在人类患者中看到的重现表型的模型，以测试治疗方法，包括基因治疗和基因组编辑方法，并开发临床相关的治疗以确定这些疗法的成功。为了实现这一目标，本核心正在与项目1（Flotte），以创建条件性表达人AAT的AAT-peptide或PiZ雪貂在本发明的实施方案中，使用了人AAT（hAAT）基因敲除背景下的PiZ突变的鼠模型以及在AAT基因敲除背景下的PiZ突变的鼠模型。在我们组中创建的鼠标。敲除小鼠重现了完全缺乏AAT产生的肺表型，但是不能完全模拟具有一些残余血液的PiZ AAT患者的状态产生残余抗弹性蛋白酶活性的AAT水平。在这个核心中，我们的目标是创造和在AAT-KO背景下表征AAT-KO-PiZ小鼠，以及在AAT-KO背景下表征AAT-KO-PiZ小鼠。现有的AAT-KO/PiZ交叉鼠标。除了作为一个更相关的模型来测试基因 AAT-KO-PiZ小鼠也将作为进一步研究基因组的模型。编辑项目2中的Z-AAT等位基因（Xue）。当前的PiZ鼠标包含多个副本 PiZ基因，使其成为基因组编辑的非理想模型。两种小鼠模型都允许我们进一步阐明了PiZ突变在没有野生型小鼠基因的情况下所起的作用。 AAT，这是以前没有在小鼠中建模的东西。在核心B中，我们还将产生人源化肝NSG-PiZ小鼠以选择靶向人肝细胞的AAV血清型，项目3（王）。除了生产用于项目1、2和3的小鼠和雪貂模型外，我们还将我还与项目1和2一起工作，以表征肺表型对基因的反应，治疗和基因组编辑。核心将提供新的专门知识，在啮齿动物肺功能支气管肺泡灌洗试验和促进肺部计算机断层扫描，与Bankier博士和Tufts Cummings兽医学院合作。