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

 描述（由申请人提供）：该提案概述了为期两年的过渡赠款博士。Kubinak博士奖励准则规定，一旦Kubinak博士开始在一个研究机构担任助理教授，这项赠款就开始生效，资金将用于支持他头两年的工作。Kubinak博士目前是June L博士实验室的博士后研究员。Round博士在犹他州大学。Kubinak博士的研究重点是了解控制肠道微生物抗体反应的免疫机制，以及改变宿主-微生物群关系如何导致疾病。Kubinak博士最近证明，T细胞中Toll样受体（TLR）信号传导的中断改变了肠道中抗体介导的选择，导致肠道免疫应答的建立。 更容易引起炎症的微生物群他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“微生物自我”，从而解释个体之间的疾病易感性模式。沿着经典的免疫学方法，Kubinak博士一直在采用下一代测序方法来表征个体之间的微生物群群落，以及宿主MHC基因型对肠道中免疫球蛋白（IG）库发育的选择模式的影响。他的数据表明，MHC抗原呈递和MHC多态性的丧失与肠道微生物群组成的急剧变化有关，这与针对肠道菌群的抗体应答的多种表型差异有关。更重要的是，他也有数据表明，MHC介导的肠道感染易感性模式取决于MHC如何在个体中形成独特的群落。Kubinak博士正在寻求以他的博士后工作为基础，了解TLR和MHCII信号传导如何在B细胞中会聚，以指导针对抗体的抗体反应。这两种途径在产生多克隆低亲和力抗体的T细胞非依赖性（TI）B细胞应答和产生单克隆高亲和力抗体的T细胞依赖性（TD）B细胞应答之间偏斜。为了对比这两种途径对体内抗肿瘤抗体应答的重要性，将开发两种B细胞条件性敲除小鼠，其TLR信号传导（MYD 88 fl/flCD 19 cre+）或MHCII呈递（MHCIIfl/flCD 19 cre+）被敲除。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-偏斜表型）或MHC呈递肽（模拟TD-偏斜表型）而成熟。这些模型将用于对比TI与TD偏倚反应如何影响伊加库选择和IgA介导的肠道物种靶向，这如何影响微生物群组成，以及改变的微生物群群落如何差异地影响对炎症和传染性肠道疾病的易感性。最后，D. Kubinak还将讨论暴露于无处不在的环境污染物（双酚A）是否会影响破坏正常的伊加库选择，以促进致病微生物群。本提案中概述的工作旨在阐明自然选择在肠道中形成IG库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理论在理解宿主健康方面的一种新的应用，可以产生治疗人类疾病的新疗法。 Kubinak博士的博士和博士后生涯专注于了解宿主-微生物共生的因素。在他的博士后培训期间提供给他的专业环境有助于推动他理解进化理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，Kubinak博士的长期职业目标是加强进化理论在医学中的应用。要做到这一点，我的职业发展计划的一个主要组成部分将是与基础科学家以及临床医生形成富有成效的合作关系，并促进教育机会，让学生获得进化理论的实际应用经验，以了解和治疗人类疾病。

 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.