Leptin and B cell Function

瘦素和B细胞功能

• 批准号: 7687358
• 负责人: GIOVANNI FRANCHIN
• 金额: $ 14.5万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687358
• 关键词: Address; Adoptive Transfer; Affect; Affinity; Antibodies; Antibody Formation; Apoptosis; Architecture; Area; Award; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Cell physiology; Cells; Cellular biology; Data; Defect; Dendritic Cells; Diet; Docking; Educational Activities; Endocrine; Ethics; Experimental Designs; Ficoll; Flow Cytometry; Frequencies; Glucose; Goals; Grant; Heavy-Chain Immunoglobulins; Hematopoiesis; Homeostasis; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; In Vitro; Institution; K-Series Research Career Programs; Knowledge; Leptin; Leptin deficiency; Light; Link; MAP Kinase Gene; Measures; Mediating; Medicine; Metabolic; Metabolic syndrome; Metabolism; Modeling; Mus; Obese Mice; Obesity; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphotransferases; Physiology; Principal Investigator; Production; Protein Tyrosine Kinase; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant Cytokines; Recombinants; Recruitment Activity; Research; Role; Serum; Signal Pathway; Signal Transduction; Site; Spleen; T-Lymphocyte; Testing; Training; Transgenic Organisms; Wild Type Mouse; angiogenesis; anti-IgG; career; db/db mouse; design; enzyme linked immunospot assay; experience; immune function; in vivo; insulin secretion; leptin receptor; lipid metabolism; macrophage; receptor; receptor-mediated signaling; reconstitution; release of sequestered calcium ion into cytoplasm; research study; response; skills; statistics

DESCRIPTION (provided by applicant): This application for a Career Development Award (K08) is designed to study how leptin affects B cell function. The applicant has generated preliminary data demonstrating a defective humoral response to NP immunization (both T-dependent and T-independent) in leptin deficient (ob/ob) or leptin receptor deficient (db/db) mice. Naive ob/ob and db/db mice display an abnormal distribution of B cell subsets and decreased levels of basal serum immunoglobulin (Ig) G when compared to wild type mice. In addition, ELISPOT analysis following immunization with NP-Ficoll (T-independent response) revealed increased numbers of NP-specific IgM, but not IgG B cells in ob/ob and db/db mice, in contrast with significantly lower levels of serum IgM or IgG anti-NP antibodies. These results demonstrate in mice which lack leptin signaling in vivo, more B cells become activated after NP-Ficoll immunization however they seem to have reduced secretion of antibodies or produce antibodies with lower affinities than wild type suggesting a defect in repertoire selection or perhaps in class switching. We propose three specific aims that will address the following assumptions: (1) we hypothesize that in the absence of leptin signaling, there is a defect in B cell function; (2) we propose that the defect in B cell function in the absence of leptin signaling is, at least in part, B cell intrinsic. This hypothesis is supported by our observation that an impaired humoral response to NP is transferable to RAG2-/- mice by adoptive transfer of ob/ob or db/db B cells; (3) we theorize that leptin signaling can cross talk with B cell receptor (BCR) signaling pathways. The training plan will allow the applicant to acquire new knowledge of methodological approaches to B cell biology and the proposal will broaden our understanding of the interplay between metabolic states and immunity. The training goals will be accomplished through the completion of the research plan and educational activities in the area of endocrine/metabolism physiology, experimental design, statistics and ethics. The training experiences in this award will provide the applicant with the necessary skills and experiences to independently undertake a career in investigative medicine and effectively compete for independent grant support in his current institution or elsewhere.

描述（由申请人提供）：本职业发展奖（K08）旨在研究瘦素如何影响B细胞功能。申请人产生了初步数据，表明在瘦素缺乏（OB/OB）或瘦素受体缺乏症（DB/DB）小鼠中对NP免疫（T依赖性和T依赖性）的体液反应有缺陷。与野生型小鼠相比，天真的OB/OB/OB/DB/DB小鼠表现出异常的B细胞亚群和基底血清免疫球蛋白（Ig）G的分布。此外，用NP-FICOLL进行免疫后的ELISPOT分析（T独立响应）显示，与血清IgM或IgG抗NP抗体的水平显着较低，OB/OB和DB/DB小鼠中NP特异性IGM的数量增加，但没有增加IgG B细胞。这些结果表明，在体内缺乏瘦素信号传导的小鼠中，在NP-FICOLL免疫后，更多的B细胞被激活，但是它们似乎降低了抗体的分泌或产生与野生类型低相关的抗体的分泌，比野生类型较低，表明在曲目选择中存在缺陷或可能在类交换中。我们提出了三个特定的目标，该目标将解决以下假设：（1）我们假设在没有瘦素信号传导的情况下，B细胞功能存在缺陷； （2）我们提出，在没有瘦素信号传导的情况下，B细胞功能的缺陷至少部分是B细胞固有的。我们的观察结果支持了这一假设，即通过ob/ob或ob或db/db b细胞的产物转移，对NP的体液反应受损可转移至rag2 - / - 小鼠。 （3）我们从理论上认为瘦素信号传导可以与B细胞受体（BCR）信号通路交叉。培训计划将使申请人获得B细胞生物学方法学方法的新知识，该提案将扩大我们对代谢状态与免疫力之间相互作用的理解。培训目标将通过在内分泌/代谢生理，实验设计，统计和道德领域的研究计划和教育活动完成。该奖项的培训经验将为申请人提供独立从事调查医学职业的必要技能和经验，并有效地竞争其当前机构或其他地方的独立赠款支持。