Exploring how B cell Maturation Pathways Influence Microbiota Composition and Host Health

探索 B 细胞成熟途径如何影响微生物群组成和宿主健康

• 批准号: 9089576
• 负责人: Jason L Kubinak
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2017-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089576
• 关键词: Address; Affinity; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antibody Repertoire; Antibody Response; Antigen Presentation; Antigens; Appointment; Automobile Driving; Award; B-Lymphocytes; Benign; Cell Maturation; Clone Cells; Communities; Data; Defect; Development; Development Plans; Disease; Disease susceptibility; Doctor of Philosophy; Endocrine Disruptors; Enteral; Environment; Environmental Pollutants; Environmental Risk Factor; Equilibrium; Exposure to; Funding; Generations; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Guidelines; Health; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulins; Immunologic Factors; Immunologics; Individual; Infection; Inflammatory; Institution; Knock-out; Knockout Mice; Laboratory Research; Ligands; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mature B-Lymphocyte; Mediating; Medicine; Methods; Microbe; Modeling; Mucous body substance; Natural Selections; Pathway interactions; Pattern; Peptides; Phenotype; Physiological; Physiology; Plasma Cells; Predisposition; Process; Production; Receptor Signaling; Research; Role; Scientist; Shapes; Signal Transduction; Students; Symbiosis; T-Lymphocyte; Technology; Testing; Toll-like receptors; Universities; Utah; Work; bisphenol A; career; career development; commensal microbes; cost; density; experience; experimental study; gut microbiota; human disease; in vivo; insight; microbial; microbial community; microbiota; mouse model; next generation sequencing; novel; novel therapeutics; polyclonal antibody; post-doctoral training; practical application; professor; public health relevance; response; theories

 DESCRIPTION (provided by applicant): This proposal outlines a two-year transitional grant for Dr. Jason L. Kubinak, Ph.D. Award guidelines stipulate that this grant becomes active once Dr. Kubinak begins his appointment as an assistant professor at a research institution, and that the funds will be used to support his first two years of work. Dr. Kubinak is currently a postdoctoral research fellow in the lab of Dr. June L. Round, Ph.D. at the University of Utah. Dr. Kubinak's research focuses on understanding the immune mechanisms controlling antibody responses against commensal microbes in the gut and how altered host-microbiota relationships contribute to disease. Dr. Kubinak has recently demonstrated that disruptions to Toll-like receptor (TLR) signaling in T cells alters antibody-mediated selection in the gut that results in establishment of a more pro- inflammatory microbiota. He is now focused on understanding whether polymorphism at major histocompatibility complex (MHC) genes, can promote a "microbial self" that explain patterns of disease susceptibility among individuals. Along with classic immunological methods, Dr. Kubinak has been employing next-generation sequencing approaches to characterize microbiota communities among individuals as well as the effect of host MHC genotype on patterns of selection on developing immunoglobulin (Ig) repertoires in the gut. His data indicates that loss of MHC antigen presentation, and MHC polymorphisms, are associated with dramatic shifts in gut microbiota composition and that this is associated with multiple phenotypic differences in antibody responses against commensals. More importantly, he also has data indicating that MHC-mediated patterns of susceptibility to enteric infection are dependent on how MHC shapes unique communities among individuals. For this proposal Dr. Kubinak is seeking to build off of his postdoctoral work to understand how TLR and MHCII signaling converges in B cells to direct antibody responses against commensals. These two pathways skew between T cell-independent (TI) B cell responses generating polyclonal low-affinity antibodies, and T cell-dependent (TD) B cell responses generating monoclonal high-affinity antibodies. To contrast the importance of these two pathways on antibody responses against commensals in vivo, two B cell conditional knockout mice will be developed that have TLR signaling (MYD88fl/flCD19cre+) or MHCII presentation (MHCIIfl/flCD19cre+) knocked out. This will produce two mouse models where B cells mature in response to TLR ligands (modelling a TI- skewed phenotype) or MHC-presented peptides (modelling a TD-skewed phenotype), respectively. These models will be used to contrast how TI- versus TD-biased responses influence IgA repertoire selection and IgA-mediated targeting of commensal species, how this influences microbiota composition, and how altered microbiota communities differentially influence susceptibility to inflammatory and infectious enteric diseases. Finally, D. Kubinak will also address whether exposure to a ubiquitous environmental pollutant (Bisphenol A) can influence disrupt normal IgA repertoire selection to promote a disease-causing microbiota. The work outlined in this proposal seeks to elucidate the mechanism of natural selection on developing Ig repertoires in the gut and the relevance of the microbiota to this process. This work represents a novel application of evolutionary theory to understanding host health that could yield novel therapies for the treatment of human disease. Dr. Kubinak has spent his doctoral and postdoctoral career focused on understanding the factors governing host-microbe symbiosis. The professional environment provided to him during his postdoctoral training has been instrumental in driving him to understand how evolutionary theory can help us better understand why disease happens. Beyond creating a vibrant and successful research laboratory in the short-term with the experiments described above, Dr. Kubinak's long-term career goal is to enhance the use of evolutionary theory in medicine. To do this, a major component of my career development plan will be to form productive collaborative relationships with basic scientists as well as clinicians, and to promote educational opportunities for students to gain experience in the practical application of evolutionary theory to the understanding and treatment of human disease.

 描述（由申请人提供）：该提案概述了为 Jason L. Kubinak 博士提供的为期两年的过渡性资助。 奖励指南规定，一旦 Kubinak 博士开始担任研究助理教授，该资助将立即生效。 Kubinak 博士目前是犹他大学 June L. Round 博士实验室的博士后研究员。 Kubinak 的研究重点是了解控制针对肠道共生微生物的抗体反应的免疫机制，以及宿主与微生物群关系的改变如何导致疾病。 Kubinak 博士最近证明，T 细胞中 Toll 样受体 (TLR) 信号的破坏会改变抗体。 - 肠道中介导的选择导致建立 Kubinak 博士现在专注于了解主要组织相容性复合体 (MHC) 基因的多态性是否可以促进“微生物自身”，从而解释个体之间的疾病易感性模式。他的数据一直在采用新一代测序方法来表征个体中的微生物群落，以及宿主 MHC 基因型对肠道中免疫球蛋白 (Ig) 库的选择模式的影响。表明 MHC 抗原呈递和 MHC 多态性的丧失与肠道微生物群组成的巨大变化有关，并且这与针对共生体的抗体反应的多种表型差异有关。更重要的是，他还有数据表明 MHC 介导的模式。肠道感染的易感性取决于 MHC 如何在个体中形成独特的群落。对于这项建议，Kubinak 博士试图在其博士后工作的基础上了解 TLR 和 MHCII 信号如何在 B 细胞中汇聚。这两条途径在产生多克隆低亲和力抗体的 T 细胞依赖性 (TI) B 细胞反应和产生单克隆高亲和力抗体的 T 细胞依赖性 (TD) B 细胞反应之间存在偏差。鉴于这两种途径对体内针对共生体的抗体反应的重要性，将开发两种具有 TLR 信号传导 (MYD88fl/flCD19cre+) 或 MHCII 表达的 B 细胞条件敲除小鼠(MHCIIfl/flCD19cre+) 敲除，这将产生两种小鼠模型，其中 B 细胞分别响应 TLR 配体（模拟 TI 偏向表型）或 MHC 呈递肽（模拟 TD 偏向表型）。用于对比 TI 与 TD 偏向反应如何影响 IgA 库选择和 IgA 介导的共生物种靶向，以及这如何影响微生物群组成，最后，D. Kubinak 还将探讨暴露于普遍存在的环境污染物（双酚 A）是否会破坏正常的 IgA 库选择，从而促进致病微生物群的产生。该提案中概述的目的旨在阐明自然选择在肠道中发展 Ig 库的机制以及微生物群与这一过程的相关性。库比纳克博士的工作代表了进化理论在理解宿主健康方面的新颖应用，这可能会产生治疗人类疾病的新疗法。库比纳克博士的博士和博士后生涯专注于理解控制宿主与微生物共生的因素。库比纳克博士在博士后培训期间的学习有助于他理解进化论如何帮助我们更好地理解疾病发生的原因。 除了通过上述实验在短期内创建一个充满活力和成功的研究实验室外，库比纳克博士的长期研究职业目标是提高为此，我职业发展计划的一个主要组成部分将是与基础科学家和冠军建立富有成效的合作关系，并为学生提供获得进化论实际应用经验的教育机会。理解和治疗人类疾病的理论。