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

定义人类胎儿从胎儿到成人 T 细胞优势的转变

• 批准号: 8607580
• 负责人: Trevor Deon Burt
• 金额: $ 12.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607580
• 关键词: Address; Admixture; Adult; Affect; Antibodies; Antigens; Applications Grants; Award; Basic Science; Birth; Bone Marrow; CD34 gene; CD4 Positive T Lymphocytes; California; Cells; Cellular biology; Characteristics; Childhood; Clinical; Clinical Research; Communicable Diseases; Data; Development; Discipline of obstetrics; Disease; Ensure; Environment; Fetal Liver; Fetus; Flow Cytometry; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Gynecology; Hematopoietic; Hepatitis B Vaccination; Human; Human Characteristics; Human Development; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunologics; Immunology; In Vitro; Infant; Infection; Knowledge; Laboratories; Lead; Life; Measurement; Measures; Mediating; Medicine; Mentors; Messenger RNA; Molecular Profiling; Nature; Neonatal; Neonatology; Newborn Infant; Normal Range; Outcome; Pathology; Pediatrics; Phenotype; Play; Population; Predisposition; Pregnancy; Prevention strategy; Process; Public Health; Publishing; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Sampling; San Francisco; Science; Severities; Source; Stem cells; Stimulus; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Time; Translational Research; Umbilical Cord Blood; Universities; Vaccination; Vaccines; Variant; base; career; cytokine; design; disability; fetal; human stem cells; immune function; in vivo; neonatal death; neonate; pathogen; patient oriented; patient oriented research; professor; progenitor; public health relevance; reproductive; response; skills; stem; stem cell biology

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.

描述（由申请人提供）：这是 Trevor Burt 博士的 K08 奖申请，他是加州大学旧金山分校 (UCSF) 新生儿科儿科助理教授，正在将自己定位为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 博士提供实现以下目标所需的支持：(1) 确定造血干/祖细胞 (HSPC) 的明确基因表达特征，从而产生独特的胎儿 (TF) 和成人 (TA) T 细胞，并使用这些 HSPC 及其子代 T 细胞的基因表达特征； (2) 定义足月人类新生儿中 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) 如何影响新生儿的免疫反应； (3) 获得人类干细胞生物学方面的专业知识，为研究胎儿和成人 HSPC 群体的调节、分化和功能做好准备； (4) 获得规划和执行儿科患者导向研究的专业知识，从而发展作为转化研究者的独立研究生涯。为了实现这些目标，伯特博士组建了一个指导团队，其中包括一名主要导师、加州大学旧金山分校实验医学部主任 Joseph“Mike”McCune 博士，他在传染病和人类免疫系统个体发育方面进行基础和转化研究，以及两名辅助导师：苏珊·费舍尔博士，产科、妇科和生殖科学教授，在人类领域拥有具体专业知识。 HSPC生物学； Jennifer Puck 博士是儿科教授兼加州大学旧金山分校儿科临床研究中心主任，拥有人类免疫学和儿科转化研究方面的专业知识。人们对人类免疫系统的发育，特别是从胎儿耐受性免疫反应到成人免疫反应性免疫反应的转变知之甚少。为了最终解决胎儿和新生儿感染和免疫特有的问题，我们必须首先研究这一转变的正常过程。这里提出的研究旨在回答这个问题：胎儿和成人 T 细胞在当时或出生时存在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？ Burt 博士将利用 UCSF 提供的资源来： 确定 CD34 中明确的基因表达谱？产生胎儿和成人 T 细胞的 HSPC（目标 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 T 细胞免疫的体外测量（目标 2），并通过研究 T 细胞混合物对新生儿疫苗接种反应的影响，将这些发现扩展到 T 细胞免疫的体内测量（目标 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，他最终将研究控制从胎儿到成人 T 细胞优势转变的基本调控过程，以及这些过程中的畸变如何与胎儿和新生儿的病理学相关。 公共卫生相关性：项目叙述 即使在儿童广泛接种疫苗的时代，新生儿时期的感染仍然是新生儿死亡和疾病的主要原因，并且由于其可能导致的长期残疾而构成重大的公共卫生负担。人类胎儿和新生儿免疫系统的独特性质导致其对免疫和感染的反应较弱，人们对这种现象知之甚少且研究不足。明确这种弱免疫反应背后的因素将有助于减轻新生儿传染病的负担，因为可以开发出适合新生儿免疫系统的更好的疫苗和治疗方法，从而降低新生儿感染的频率和严重程度。