Mouse models of severe combined immunodeficiencies

严重联合免疫缺陷小鼠模型

• 批准号: 7614101
• 负责人: Frederick W. Alt
• 金额: $ 47.73万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614101
• 关键词: Abelson murine leukemia virus; Affect; Age; Antibodies; B-Cell Development; B-Lymphocytes; Boston; Cell Count; Cell Line; Cells; Child; Code; Collaborations; Complex; DNA; DNA Damage; DNA ligase IV; Data; Defect; Development; Disease; Embryo; Event; Family Research; Fibroblasts; Floor; Funding; Genes; Genomic Instability; Genomics; Goals; Human; Human Resources; Immune; Immune response; Immune system; Immunity; Immunodeficiency and Cancer; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunologic Deficiency Syndromes; Incidence; Infection; Instruction; Ionizing radiation; Knock-in Mouse; LIG4 gene; Laboratories; Last Name; Lead; Ligase; Lymphocyte; Malignant Neoplasms; Mature B-Lymphocyte; Modeling; Mus; Mutant Strains Mice; Mutation; Names; Neurologic; Neurons; Oncogenic; Paste substance; Pathway interactions; Patients; Pediatric Hospitals; Phenotype; Point Mutation; Predisposition; Principal Investigator; Process; Proteins; Radiation Tolerance; Radio; Research; Research Personnel; Role; Severe Combined Immunodeficiency; Staging; Stem cells; Syndrome; System; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; Tumor Suppressor Proteins; V(D)J Recombination; artemis; base; cell type; embryonic stem cell; human disease; immunodeficient mouse model; in vivo; interest; lymphoid neoplasm; mouse model; mutant; novel; null mutation; programs; protein function; repaired; response; tumor; tumorigenesis

V(D)J recombination defects underlie diseases ranging from immunodeficiency and auto-immunity to cancer. Human SCIDs result either from defects in T cell development or both T and B cell development. The latter disease, referred to as T'B'SCID, generally results from V(D)J recombination defects. Null mutations in RAG-1 or RAG-2 are the basis for about half of the human TB'SCIDs. Hypomorphic RAG mutations also cause Omenn syndrome (OS), a rare autosomal recessive SCID that often presents as a "complex" immunodeficiency with an auto-immune component. Mechanisms by which RAG mutations lead to OS are unknown. A major aim of this application is to elucidate normal RAG functions and aberrant RAG activities that could lead to complex immunodeficiency and cancer by characterizing RAG mutant mouse lines. We have generated mice that lack both the "non-core" RAG1 and RAG2 regions implicated in suppressing transpositions and a mouse carrying a RAG1 point mutation that has a potential joining defect that may predispose to oncogenic translocations. We will continue analyses of these mice and also generate additional RAG knock-in mutations including several proposed to allow RAG cutting but impaired joining. We also will employ a novel Abelson Murine Leukemia virus (A-MuLV)-transformed pro-B cell line system as a rapid in vivo screen for mutations of interest and as a basis for mechanistic analyses of RAG protein functions. The other half of human TB'SCIDs have normal RAG proteins; but show V(D)J recombination defects and increased ionizing radiation-sensitivity. The defects underlying this subset are mutations in genes that encode the Artemis, XLF and DMALigase 4 non-homologous DMA end-joining factors. Human Artemis mutations completely inactivate the gene; whereas human Lig4 mutations are all hypomorphic. It is not yet clear whether known human XLF mutations completely inactivate the gene. We previously generated a mouse model for Artemis deficiency and recently generated mouse models for both XLF and hypomorphic Ligase 4 deficiency. The other major aims of this proposal are to characterize these new models to elucidate normal functions of these NHEJ factors and, again, to determine how mutations in these genes contribute to various human immunodeficiency syndromes and potentially to cancer. Our immune system recognizes and eliminates a vast array of foreign invaders based on a process in which limitless numbers of antibody genes are formed by cutting and pasting gene cassettes. Defects in human genes that code for proteins that carry out this cutting and pasting process cause immunodeficiency (susceptibility to infection). Our proposed research seeks to make mouse models for such human diseases to better understand the functions of the cutting and pasting proteins and to develop better therapies. Children's Hospital Karp Family Research Laboratories 9th Floor One Blackfan Circle Boston, MA 02115 PHS 398 (Rev. 04/06) Page Form Page 2 Principal Investigator/Program Director (Last, First, Middle): TeitlOrst, ComeliS P.I Alt, Frederick W. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shownbelow. Start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first. Name eRA CommonsUser Name Organization Role onProject Alt, Frederick W. FREDALT Children'

V(D)J重组缺陷是免疫缺陷和自身免疫等疾病的基础