mtDNA depleter mouse for decoding mitochondrial regulation of diverse organs

mtDNA 消耗小鼠用于解码不同器官的线粒体调节

基本信息

批准号：
10352486
负责人：
KESHAV K SINGH
金额：
$ 22.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352486
关键词：
Address Adopted Affect Aging Alanine Animal Model Animals Area Aspartic Acid Atrophic Biocompatible Materials Cardiovascular system Cell Death Cell Proliferation Cells Cellular Metabolic Process Child Development DNA DNA biosynthesis DNA polymerase gamma DNA-Directed DNA Polymerase Defect Development Diabetes Mellitus Disease Dominant-Negative Mutation Doxycycline Female Foundations Functional disorder Gene Expression Genetically Modified Animals Goals Health Heart Human Human Development Hypertrophy Impairment Institutes Kidney Light Liver Malignant Neoplasms Mitochondria Mitochondrial DNA Mitochondrial DNA depletion syndromes Mitochondrial Diseases Mus Mutation National Cancer Institute National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Disease National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Neurological Disorders and Stroke National Institute on Aging Nuclear Obesity Organ Oxidative Phosphorylation Pathology Play Ploidies Polymerase Positioning Attribute Production Regulation Reporting Research Research Personnel Role Signal Transduction Spleen System Testing Tissues United States National Institutes of Health Women&apos s Health age related animal model development base biological adaptation to stress body system driving force human disease improved in vivo interest male mitochondrial dysfunction mouse model mutant nervous system disorder operation reproductive organ response skin organogenesis

项目摘要

This application is responsive to PAR-19-369 “Development of Animal Models and Related Biological Materials for Research R21,” which seeks application to develop animal models that are applicable to the research interests of multiple NIH institutes. It addresses one of the objective “Characterization of new and significantly improved genetically modified animal models that are applicable to diseases that impact multiple body systems, e.g., animal models with mitochondrial defects.” Impaired mitochondrial function is associated with many primary mitochondrial diseases in which mitochondrial dysfunction is the primary cause of the disease. Notably, mtDNA depletion syndromes (MDS) are characterized by a severe reduction in mtDNA content leading to impaired mitochondrial function in affected tissues and organs. Secondary mitochondrial diseases in which mitochondria are secondarily involved include cardiovascular, diabetes, obesity, neurological disorders, and cancer. Moreover, a general decline in mitochondrial function is extensively reported during aging and is known to be a driving force underlying age-related human diseases. Despite the enormous importance of mitochondria in the optimal function of various organs, the in vivo role of mitochondria in the vast majority of mammalian organs remain unknown. Mitochondrial DNA polymerase γ (POLG1) is the only DNA polymerase involved in the synthesis of mtDNA. We developed an inducible mouse expressing, in the polymerase domain of POLG1, a dominant-negative (DN) mutation (an aspartic acid to alanine (D to A) mutation at position 1135, that induces depletion of mtDNA in the whole animal. Our preliminary studies suggest that impaired mitochondrial function in the whole animal results in multisystem dysfunction. These include the development of skin wrinkles and hypertrophy of the liver, kidney, heart and spleen. Furthermore, mtDNA depleter mice show atrophy of male and female reproductive organs. Based on these observations, we hypothesize that the characterization of mtDNA depleter mice will facilitate the understanding of the vital function of mitochondria in the development and function of multiple organ systems. We propose two specific aims to test this hypothesis: Aim 1: Determine the organ-specific hypertrophic and atrophic pathology associated with mitochondrial dysfunction in mtDNA depleter mouse Aim 2: Identify organ specific mitochondrial stress response mechanisms underlying hypertrophy and atrophy. Our long-term goal is to enable the widespread use of this mouse model, which will accelerate mitochondrial research across various organs and diseases. The mouse will be useful in diverse research areas relevant to the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Heart, Lung and Blood Institute, the National Institute of Child and Human Development, and the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, the National Institute of Allergy and Infectious Diseases and Center for Women’s health.

该应用程序响应 PAR-19-369“动物模型和相关生物学的开发” 研究材料 R21”，寻求应用来开发适用于它涉及多个 NIH 研究所的研究兴趣，其目标之一是“新的和新的特征的表征”。显着改进的转基因动物模型适用于影响多种疾病的疾病身体系统，例如线粒体功能受损的动物模型。” 与许多原发性线粒体疾病相关，其中线粒体功能障碍是主要原因值得注意的是，mtDNA 耗竭综合征 (MDS) 的特点是 mtDNA 严重减少。导致受影响组织和器官中线粒体功能受损的次级线粒体。线粒体继发性参与的疾病包括心血管、糖尿病、肥胖、神经系统疾病此外，衰老过程中线粒体功能普遍下降。尽管它非常重要，但已知它是与年龄相关的人类疾病的驱动力。线粒体在各个器官中发挥最佳功能，线粒体在体内的绝大多数作用哺乳动物器官中的线粒体 DNA 聚合酶 γ (POLG1) 是唯一的 DNA 聚合酶。我们在聚合酶结构域中开发了一种可诱导的小鼠表达。 POLG1，显性失活 (DN) 突变（第 1135 位的天冬氨酸到丙氨酸（D 到 A）突变，我们的初步研究表明线粒体受损。整个动物的功能会导致多系统功能障碍，其中包括皮肤皱纹的形成。此外，mtDNA 消耗小鼠的肝脏、肾脏、心脏和脾脏也出现萎缩。根据这些观察，我们认为男性和女性的生殖器官。 mtDNA 消耗小鼠的表征将有助于了解 mtDNA 的重要功能我们提出了两个具体的线粒体在多个器官系统的发育和功能中的作用。旨在检验这一假设：目标 1：确定器官特异性肥大和萎缩与 mtDNA 消耗小鼠线粒体功能障碍相关的病理学目标 2：识别器官特异性线粒体应激反应机制是肥大和萎缩的基础。我们的长期目标是使这种小鼠模型得到广泛使用，这将加速线粒体小鼠将在与各种器官和疾病相关的多个研究领域发挥作用。国家糖尿病、消化和肾脏疾病研究所、国家老龄化研究所、国家心脏、肺和血液研究所、国家儿童和人类发展研究所以及国家神经疾病和中风研究所、国家癌症研究所、国家过敏研究所以及传染病和妇女健康中心。