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（申请提供）：该提案概述了Jason L. Kubinak博士的两年过渡赠款。奖励指南规定，一旦Kubinak博士开始任命研究机构的助理教授，该赠款将变得活跃，并且资金将用于支持他的前两年工作。 Kubinak博士目前是June L. Round博士博士博士实验室的博士后研究员。在犹他大学。 Kubinak博士的研究重点是理解控制肠道中共生微生物抗体反应的免疫机制，以及宿主 - 微生物群的改变如何导致疾病。 Kubinak博士最近证明，T细胞中对Toll样受体（TLR）信号的破坏会改变肠道中的抗体介导的选择，从而导致建立 一种更促炎性的微生物群。现在，他专注于了解主要组织相容性复合物（MHC）基因的多态性是否可以促进“微生物自我”，从而解释个体中疾病易感性的模式。除了经典的免疫学方法外，库比纳克博士一直使用下一代测序方法来表征个体之间的微生物群落，以及宿主MHC基因型对肠内免疫球蛋白（Ig）的选择模式的影响。他的数据表明，MHC抗原表现和MHC多态性的丧失与肠道菌群组成的急剧变化有关，这与针对抗验室的抗体反应的多种表型差异有关。更重要的是，他还拥有数据，表明MHC介导的对肠感染的易感性模式取决于MHC如何形成个体中独特的社区。对于这一建议，Kubinak博士正在寻求建立他的博士后工作，以了解TLR和MHCII信号如何在B细胞中收敛以指导针对共生的抗体反应。这两个途径在产生多克隆低亲和力抗体的T细胞独立（Ti）B细胞反应之间偏斜，而T细胞依赖性（TD）B细胞反应产生了单克隆高亲和力的抗体。为了将这两种途径在体内针对共生的抗体反应上的重要性，将开发两只具有TLR信号传导（MYD88FL/FLCD19CRE+）或MHCII呈现（MHCIIFL/FLCD19CRE+）的B细胞有条件的敲除小鼠。这将产生两种小鼠模型，其中B细胞分别响应TLR配体（建模ti-skewed表型）或MHC呈现的肽（分别建模TD链式表型）。这些模型将用于对比TI-ti偏置反应如何影响IgA曲目选择和IgA介导的共生物种的靶向，这如何影响微生物群的组成以及微生物群落的改变对炎症性和感染性肠道疾病的敏感性有所不同。最后，D。kubinak还将解决暴露于普遍存在的环境污染物（双酚A）是否会影响破坏正常的IgA曲目选择以促进引起疾病的微生物群。该提案中概述的工作旨在阐明自然选择在肠道中开发Ig曲目的机制以及微生物群与此过程的相关性。这项工作代表了进化论了解宿主健康的一种新颖应用，可以产生新的治疗人类疾病疗法。 Kubinak博士将他的博士学位和博士后职业都集中在理解有关主机象征的因素上。在博士后培训期间提供给他的专业环境有助于他了解进化论如何帮助我们更好地理解疾病的发生。除了上述实验的短期内创建一个充满活力，成功的研究实验室外，库比纳克博士的长期职业目标是增强进化论在医学中的使用。为此，我职业发展计划的一个主要组成部分是与基础科学家和临床医生建立富有成效的合作关系，并为学生促进教育机会，从而获得进化论在理解和治疗人类疾病的实际应用方面获得经验。