Defining Transition from Fetal to Adult T Cell Predominance in the Human Fetus

描述（由申请人提供）：这是一份为Trevor Burt博士申请K08奖的申请，他是加州大学旧金山分校（UCSF）新生儿科助理教授，他是一名研究人类胎儿和新生儿免疫系统发育和功能的年轻研究者。K08奖项将为Burt博士提供必要的支持，以实现以下目标：(1)确定产生独特胎儿（TF）和成人（TA） T细胞的造血干细胞/祖细胞（HSPC）的明确基因表达特征，并使用这些HSPC及其后代T细胞的基因表达特征；(2)确定足月人类新生儿TF和TA混合程度的正常变异性，并确定出生时它们的相对频率（TF/TA）如何影响新生儿免疫反应；(3)获得人类干细胞生物学方面的专业知识，这将为他研究胎儿和成人HSPC群体的调控、分化和功能做好准备，最后；(4)获得规划和执行儿科患者导向研究的专业知识，从而发展独立的研究事业，成为一名转化研究者。为了实现这些目标，Burt博士组建了一个指导团队，其中包括一位主要导师Joseph“Mike”McCune博士，他是UCSF实验医学部主任，负责传染病和人类免疫系统个体发生的基础和转化研究，以及两位共同导师：Susan Fisher博士，妇产科和生殖科学教授，具有人类HSPC生物学的专业知识；Jennifer Puck博士，儿科教授兼UCSF儿科临床研究中心主任，在人类免疫学和儿科转化研究方面具有专长。人类免疫系统的发育，特别是从胎儿耐受原性免疫反应到成人免疫反应性免疫反应的转变，人们对其了解甚少。为了最终解决胎儿和新生儿感染和免疫的具体问题，我们必须首先研究这种过渡的正常过程。这里提出的研究旨在回答这样一个问题：胎儿和成人在出生时存在的T细胞的相对频率是否与对抗原产生适应性免疫反应的能力有关？伯特博士将利用UCSF提供给他的资源：确定CD34基因表达谱？产生胎儿和成人T细胞的HSPC（目的1），表征正常足月婴儿中胎儿和成人T细胞和HSPC混合物的正常范围，以及这种混合物如何影响体外T细胞免疫测量（目的2），并通过研究T细胞混合物对新生儿疫苗应答的影响，将这些发现扩展到体内T细胞免疫测量（目的3）。这将为Burt博士提供必要的技能和初步数据，以准备R01拨款申请，他将最终研究控制从胎儿到成人T细胞优势转变的潜在调节过程，以及这些过程中的异常如何与胎儿和新生儿的病理相关。

DESCRIPTION (provided by applicant): This is an application for a K08 award for Dr. Trevor Burt, an Assistant Professor of Pediatrics in the Division of Neonatology at the University of California, San Francisco (UCSF), who is establishing himself as a young investigator in the development and function of the human fetal and neonatal immune system. This K08 award will provide Dr. Burt with the support necessary to accomplish the following goals: (1) to identify definitive gene-expression signatures for hematopoietic stem/progenitor cells (HSPC) that give rise to unique fetal (TF) and adult (TA) T cells, and using the gene-expression signatures of these HSPC and their progeny T cells; (2) to define the normal variability in the degree of TF and TA admixture in the full-term human neonate, and determine how their relative frequency (TF/TA) at birth affects neonatal immune responses; (3) to gain expertise in human stem cell biology that will prepare him to study the regulation, differentiation and function of fetal and adult HSPC populations, and finally; (4) to gain expertise in planning and executing pediatric patient-oriented research, and thereby develop an independent research career as a translational investigator. To achieve these goals, Dr. Burt has assembled a mentoring team comprised of a primary mentor, Dr. Joseph "Mike" McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts basic and translational research in infectious disease and human immune system ontogeny, and two co-mentors: Dr. Susan Fisher, a Professor of Obstetrics, Gynecology and Reproductive Sciences, who has specific expertise in human HSPC biology; and Dr. Jennifer Puck, a Professor of Pediatrics and Director of the UCSF Pediatric Clinical Research Center, who has expertise in human immunology and pediatric translational research. Development of the human immune system, and especially the transition from the fetal tolerogenic immune response to the adult immunoreactive immune response is very poorly understood. To ultimately address problems that are specific to infection and immunization in the fetus and neonate, we must first study the normal process of this transition. The studies proposed here are designed to answer the question: is the relative frequency of fetal and adult T cells that are present at the time or birth related to the ability to mount an adaptive immune response to antigens? Dr. Burt will use the resources available to him at UCSF to: identify definitive gene expression profiles in the CD34? HSPC that give rise to fetal and adult T cells (Aim 1), characterize the normal range of fetal and adult T cell and HSPC admixture in normal full-term infants and how this admixture affects in vitro measures of T cell immunity (Aim 2), and to extend these findings to in vivo measurement of T cell immunity by studying the effects of T cell admixture on responses to neonatal vaccination (Aim 3). This will provide Dr. Burt the necessary skills and preliminary data to prepare an R01 grant application in which he will ultimately study the underlying regulatory processes that govern the transition from fetal to adult T cell predominance, and how aberrations in these processes may relate to pathology in the fetus and newborn. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Even in the era of widespread childhood vaccination, infection in the newborn period remains a leading cause of neonatal death and disease, and represents a significant public health burden due to long-term disabilities that can result from it. The unique nature of the human fetal and newborn immune system causes it to respond weakly to immunization and infections, a phenomenon that is poorly understood and greatly understudied. Defining the factors behind this weak immune response will help to alleviate the burden of neonatal infectious disease by leading to the creation of better vaccines and treatments, tailored to the newborn immune system, that will reduce the frequency and severity of infections in the newborn.