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

• 批准号: 10589093
• 负责人: KESHAV K SINGH
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589093
• 关键词: Acceleration; 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 polymerase gamma; DNA-Directed DNA Polymerase; Darkness; 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; 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; Polymerase; Positioning Attribute; Production; Regulation; Reporting; Research; Research Personnel; Role; Signal Transduction; Skin Wrinkling; Spleen; System; Testing; Tissues; United States National Institutes of Health; Women' s Health; age related; animal model development; 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

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.

该应用响应于19-369年的“动物模型和相关生物学的开发 研究R21的材料，“寻求应用于适用于该模型的动物模型 多个NIH机构的研究兴趣。它谈到了目标“新和 显着改善了适用于影响多重疾病的一般修饰的动物模型 人体系统，例如，有线粒体缺陷的动物模型。“线粒体功能受损是 与许多主要的线粒体疾病相关，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）的特征是mtDNA严重降低 含量导致受影响组织和器官中线粒体功能受损。次级线粒体 线粒体涉及次要的疾病包括心血管，糖尿病，肥胖，神经系统 疾病和癌症。此外，在衰老期间，线粒体功能的总体下降大量报道 并且已知是与年龄有关的人类疾病的驱动力。尽管很重要 线粒体在各种器官的最佳功能中，线粒体在绝大多数的体内作用 哺乳动物器官仍然未知。线粒体DNA聚合酶γ（POLG1）是唯一的DNA聚合酶 参与MTDNA的合成。我们在聚合酶结构域中开发了一种可诱导的小鼠表达 POLG1，一种显性阴性（DN）突变（在位置1135处的天冬氨酸到丙氨酸（D到A）突变， 在整个动物中诱导mtDNA耗尽。我们的初步研究表明线粒体受损 整个动物的功能导致多系统功能障碍。这些包括皮肤包裹的发展 以及肝脏，肾脏，心脏和脾脏的肥大。此外，mtDNA复制小鼠显示出萎缩 男性和女性生殖器官。基于这些观察，我们假设 mtDNA复制小鼠的表征将有助于理解对的重要功能 线粒体在多器官系统的开发和功能中。我们提出了两个特定的 旨在检验此假设的目的：目标1：确定器官特异性肥厚和萎缩性 MTDNA复制小鼠小鼠目标中与线粒体功能障碍相关的病理学2：识别 器官特定的线粒体应力反应机制，其基础肥大和萎缩。 我们的长期目标是启用该鼠标模型的宽度使用，该模型将加速线粒体 研究各种器官和疾病。鼠标将在与该领域有关的潜水区研究领域有用 国家糖尿病与消化与肾脏疾病，国家老化研究所，国家 心脏，肺和血液研究所，国家儿童与人类发展研究所以及国家 国家癌症研究所，国家癌症研究所神经系统疾病与中风研究所 以及传染病和妇女健康中心。