Towards a Mouse Model of Complement-Mediated Diseases

补体介导疾病的小鼠模型

• 批准号: 7174295
• 负责人: Xuebin Qin
• 金额: $ 32.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174295
• 关键词: Acidosis; Acrosome Reaction; Age; Anemia; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Apoptotic; Appendix; Arthritis; Atherosclerosis; Autologous; Bacterial Infections; Binding; Blood; Blood Cells; Blood Platelets; Blood Vessels; Bone Marrow; C-terminal; Cell membrane; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Clinical Research; Colloids; Communities; Complement; Complement 3a; Complement Activation; Complement Factor B; Complement Membrane Attack Complex; Complement component C1; Complex; Complications of Diabetes Mellitus; Condition; Count; Cytolysis; Data; Deposition; Development; Diabetic Angiopathies; Disease; Endocrine; Engineering; Equilibrium; Erythrocytes; Exclusion; Exhibits; Exons; Female; Fertility; Follicle Stimulating Hormone; Generations; Genes; Genetic; Genomics; Goals; Half-Life; Hand; Hemoglobin; Hemoglobin concentration result; Hemolysis; Hemolytic Anemia; Histology; Hormones; Human; Human Pathology; Immune; Immune system; Infertility; Injection of therapeutic agent; Knock-out; Knockout Mice; Knowledge; Laboratories; Lectin; Lipopolysaccharides; Male Infertility; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Metabolic; Methods; Modeling; Modification; Molecular; Morphology; Mus; Nature; Numbers; Organ; PI-Glycan; Pathogenesis; Pathology; Pathway interactions; Penetrance; Phenotype; Physiological; Plasma; Plasma Proteins; Platelet Activation; Play; Production; Proteins; Red Blood Cell Count; Regulation; Relative (related person); Research; Reticulocyte count; Reticulocytosis; Role; Serum; Sperm Count Procedure; Staging; Structure; Syndrome; System; Testis; Testosterone; Thrombosis; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Urine; Variant; Work; base; cell injury; cell motility; citrate carrier; cobra venom factor; complement pathway; design; genetic regulatory protein; human disease; in vivo; inhibitor/antagonist; interest; link protein; male; mouse genome; mouse model; polymerization; rat Piga protein; reproductive; research study; response; size; sperm cell; time interval; tool; trait

DESCRIPTION (provided by applicant): Extensive clinical and experimental evidence strongly indicates that the complement system plays a critical role in the pathogenesis of a diverse group of human diseases that includes some of the hemolytic anemias and male infertility. Given the complex and chronic nature of these diseases in which a pathogenic role of complement still needs to be defined, molecular engineered mouse models that we propose to use in this application provide powerful tools to conduct experiments that would be impossible to perform in humans. Through three different activation pathways and formation of the membrane attack complex (MAC), the complement system mediates both acquired and innate responses to defend against bacterial infection, and to dispose of immune complexes or apoptotic cells. Activated complement and MAC can also damage self cells and thereby mediate pathological responses leading to chronic diseases. An array of complement regulatory proteins including CD59, a key inhibitor of MAC formation, have evolved to protect self cells from complement damage, which can result from either increased complement activation with MAC formation or decreased regulation. Development of adequate animal models to study the relative role of the MAC and its regulation in the pathogenesis of human diseases has been hampered because of the unexpected presence of two Cd59 genes (termed mCd59a and mCd59b) in the mouse genome. Preliminary studies on mCd59a and mCd59b knockout mice demonstrated that the mCd59ab double knockout mouse (mCdSgab-/-), which we have successfully generated by targeted deletion of both genes, was required to investigate the role of MAC regulation in the pathogenesis of human diseases. Our hypothesis is that absence of CD59 function will result in MAC-mediated tissue damage and focal pathology in different organs. Based on the phenotypic features observed in mCdSgb-/-' and mCdSgab-/- mice, we will study mCdSgab'-/- mice focusing on two phenotypic traits representative of human diseases in which a role of complement has long been suspected: 1) complement-mediated hemolytic anemia with platelet activation; and 2) male infertility. Using available C3 or C4 deficient mice, we will differentiate specific roles of complement and its activation pathways from complement-independent functions of CD59. Using transgenic mice that express hCD59 only in RBC and crossing them with mCdSgab-/-, we will verify the causal relationships between the hemolytic anemia and the loss of CD59 in mCd59ab-/-. Successful accomplishment of our goals will define the role of MAC and its regulation in three paradigmatic human diseases, and will provide the research community with a much-needed model to continue studying the role of complement in human pathology.

描述（由申请人提供）：广泛的临床和实验证据有力地表明，补体系统在包括一些溶血性贫血和男性不育症在内的多种人类疾病的发病机制中起着关键作用。考虑到这些疾病的复杂性和慢性性，其中补体的致病作用仍需要定义，我们提出在本申请中使用的分子工程小鼠模型提供了进行在人类中不可能进行的实验的强大工具。通过三种不同的激活途径和膜攻击复合物（MAC）的形成，补体系统介导获得性和先天性应答以防御细菌感染，并处理免疫复合物或凋亡细胞。激活的补体和MAC也可以损伤自身细胞，从而介导导致慢性疾病的病理反应。一系列补体调节蛋白，包括CD 59，MAC形成的关键抑制剂，已经进化到保护自身细胞免受补体损伤，这可能是由于MAC形成增加的补体激活或减少的调节。由于小鼠基因组中意外存在两个Cd 59基因（称为mCd 59 a和mCd 59 b），因此开发适当的动物模型来研究MAC及其在人类疾病发病机制中的相对作用受到阻碍。mCd 59 a和mCd 59 b基因敲除小鼠的初步研究表明，mCd 59 ab双敲除小鼠（mCdSgab-/-），我们已经成功地产生了两个基因的靶向删除，需要调查MAC调节在人类疾病的发病机制中的作用。我们的假设是，CD 59功能的缺失将导致MAC介导的组织损伤和不同器官的局灶性病理学。基于在mCdSgb-/-和mCdSgab-/-小鼠中观察到的表型特征，我们将研究mCdSgab-/-小鼠，重点关注代表人类疾病的两种表型特征，其中补体的作用长期以来一直被怀疑：1）补体介导的溶血性贫血伴血小板活化;和2）男性不育。利用现有的C3或C4缺陷小鼠，我们将区分补体及其激活途径的特定作用与CD 59的补体非依赖性功能。使用仅在RBC中表达hCD 59的转基因小鼠并将其与mCdSgab-/-杂交，我们将验证溶血性贫血与mCd 59 ab-/-中CD 59丢失之间的因果关系。我们的目标的成功实现将定义MAC的作用及其在三种典型的人类疾病中的调节，并将为研究界提供一个急需的模型，以继续研究补体在人类病理学中的作用。