Novel Gene Control of Lymphoid Tissue Development

淋巴组织发育的新基因控制

• 批准号: 7391306
• 负责人: Rosemarie E Seymour
• 金额: $ 10.17万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391306
• 关键词: Affect; Alleles; Antibody Formation; Architecture; Autoimmunity; B-Lymphocytes; Biochemistry; Bone Marrow; Candidate Disease Gene; Cell Maturation; Cell physiology; Chimera organism; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 8; Chronic; Clinical; Clinical Investigator Award; Complex; Dermatitis; Development; Developmental Biology; Disruption; Doctor of Philosophy; Embryo; Enzyme-Linked Immunosorbent Assay; Enzymes; Evaluation; Family member; Fellowship; Flow Cytometry; Follicular Dendritic Cells; Gel; Gene Chips; Gene Mutation; Genes; Genetic; Goals; Green Fluorescent Proteins; Gut associated lymphoid tissue; Homeostasis; Human; IgA Deficiency; Immune; Immune response; Immunoglobulin Class Switching; Immunohistochemistry; Immunologics; Immunology; In Situ Hybridization; Inflammation; Inflammatory; Institution; Knowledge; Laboratories; Lead; Ligands; Localized; Lymphoid; Lymphoid Tissue; Maintenance; Measures; Mentors; Molecular; Molecular Biology; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Names; Numbers; Organ; Organogenesis; Pathway interactions; Peripheral; Phenotype; Play; Precipitation; Pregnancy; Process; Production; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Relative (related person); Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Secretory Immunoglobulin A; Sequence Analysis; Signal Transduction; Signaling Molecule; Small Intestines; Spleen; Staging; Structure of aggregated lymphoid follicle of small intestine; Structure of germinal center of lymph node; Supershift Mobility Assays; Syntenic Conservation; TNF gene; Testing; Time; Tissues; Transgenic Mice; Transplantation; Veterinarians; base; chemokine; chemokine receptor; design; experience; fetal; in vivo; insight; interest; lymph nodes; lymphotoxin beta receptor; mutant; novel; oral pathogen; relB protein; research study; skin disorder; subcutaneous; transcription factor

DESCRIPTION (provided by applicant): The candidate: I am a veterinarian with a clinical background, completing a Ph.D. in biochemistry and molecular biology and a 4-year postdoctoral fellowship at The Jackson Laboratory. My primary interests are in genetics and immunology, with a long-term goal of becoming an independent research scientist. The unique opportunity offered by the K08 program to perform independent research of my own design with the guidance of experienced mentors at one of the world's premier biomedical institutions creates an ideal transition period in which to perform the valuable research described in this application and to gain the experience essential to scientific autonomy. The objective of this proposal is to identify the cellular and molecular basis of the chronic proliferative dermatitis (cpdm) mutation and to determine the role of the wildt ype allele in normal lymphoid development and function. Affected mice possess normal numbers of peripheral lymph nodes, but have multiple immunologic abnormalities including absent Peyer's patches, disorganized lymphoid architecture, diminished B cell maturation and class switching, and multi-organ inflamation. Peyer's patches are a key component of the gut-associated lymphoid tissue, which contributes to production of secretory IgA by B cells and provides the chief defense against oral pathogen invasion. IgA deficiency is a common form of immune deficiency in humans, and has also been implicated in autoimmunity. One of the goals of this research is to fill existing gaps in our current understanding of the developmental biology of Peyer's patches. Hypothesis: The gene containing the cpdm mutation is a stromal target downstream of the NF-KB transcription factor RelB/P52, and is critical for development of Peyer's patches and organization of lymphoid tissues. This gene also contributes to normal maturation and function of B cells. Specific aims: (1) Identify the gene containing the cpdm mutation, using quantitative RTPCR and direct sequencing of 21 remaining candidate genes in a 372-Kb interval, none of which has been previously implicated in lymphoid development, maintenance or function. (2) Evaluate mechanisms by which the cpdm locus contributes to Peyer's patch development, normal lymphoid organization and B cell immune responses. Significance: These studies will provide new insight into the unique developmental requirements for Peyer's patches and better understanding of the relationship between lymphoid organization and function.

描述（由申请人提供）：候选人：我是一名兽医，具有临床背景，完成博士学位。在生物化学和分子生物学和4年博士后研究员在杰克逊实验室。我的主要兴趣是遗传学和免疫学，长期目标是成为一名独立的研究科学家。K 08计划提供的独特机会，在世界领先的生物医学机构之一的经验丰富的导师的指导下，对我自己的设计进行独立研究，创造了一个理想的过渡期，在此期间进行本申请中描述的有价值的研究，并获得科学自主所必需的经验。本研究的目的是确定慢性增生性皮炎（cpdm）突变的细胞和分子基础，并确定野生型等位基因在正常淋巴发育和功能中的作用。受影响的小鼠具有正常数量的外周淋巴结，但具有多种免疫学异常，包括Peyer集合淋巴结缺失、淋巴结构紊乱、B细胞成熟和类别转换减少以及多器官炎症。派尔集合淋巴结是肠道相关淋巴组织的重要组成部分，其有助于B细胞产生分泌型伊加，并提供抵抗口腔病原体入侵的主要防御。伊加缺乏症是人类免疫缺陷的常见形式，并且也与自身免疫有关。这项研究的目标之一是填补我们目前对派尔集合淋巴结发育生物学的理解中存在的空白。假设：含有cpdm突变的基因是NF-κ B转录因子RelB/P52下游的基质靶点，并且对于派伊尔集合淋巴结的发育和淋巴组织的组织化至关重要。该基因也有助于B细胞的正常成熟和功能。具体目标：（1）使用定量RTPCR和以372-Kb间隔对21个剩余候选基因的直接测序来鉴定含有cpdm突变的基因，其中没有一个先前与淋巴发育、维持或功能有关。(2)评价cpdm基因座促进派伊尔集合淋巴结发育、正常淋巴组织和B细胞免疫应答的机制。 重要性：这些研究将为派尔集合淋巴结的独特发育要求提供新的见解，并更好地了解淋巴组织和功能之间的关系。