CD8 T Cell Dysregulation in Premature Infants

早产儿 CD8 T 细胞失调

• 批准号: 9068753
• 负责人: KRISTIN SCHEIBLE
• 金额: $ 17.97万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068753
• 关键词: Adherence; Advisory Committees; Affect; Amniotic Fluid; Antigens; Antiviral Response; Attenuated; Bacterial Infections; Biological Assay; Birth; CD8B1 gene; Cell physiology; Cells; Cellular biology; Clinical; Cluster Analysis; Cohort Studies; Cytokine Signaling; Data; Development; Development Plans; Disease; Dose; Environment; Environmental Risk Factor; Equipment; Exposure to; Fetal Development; Fetal Membranes; Fetus; Foundations; Gestational Age; Goals; Grant; Health; Homeostasis; IL8 gene; Immune; Immune response; Immune system; Immunology; In Vitro; Infant; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1; Interleukin-6; Interleukin-7; Knowledge; Leadership; Left; Life; Link; Longitudinal Studies; Measures; Mediator of activation protein; Mentors; Mentorship; Messenger RNA; Modeling; Monitor; Morbidity - disease rate; Neonatal; Organ; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphorylation; Plasma; Population; Predisposition; Pregnancy; Premature Infant; Productivity; Publishing; Research; Risk; STAT3 gene; Severity of illness; Signal Transduction; Stat5 protein; Stimulus; T cell differentiation; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Time; TimeLine; Translational Research; Umbilical Cord Blood; Umbilical cord structure; United States; Universities; Viral; Virus Diseases; Work; Writing; adaptive immunity; body system; career; career development; case control; cell behavior; cohort; collaborative environment; cytokine; design; environmental change; experience; fetal; immunopathology; improved; improved outcome; in utero; in vivo; indexing; infancy; infant morbidity; intraamniotic infection; killings; knowledge base; meetings; novel; pathogen; premature; respiratory; respiratory virus; response; skills; targeted treatment; tool

DESCRIPTION (provided by applicant): Infants born prematurely (preterm, PT) are highly susceptible to viral infections, raising questions regarding their CD8+ T cell function. Cord blood CD8+ T cells from PT infants are more highly activated and are hyper- responsive to inflammatory stimuli in vitro. The objective of this proposal is to investigate abnormalities in th cytokine milieu associated with in utero infection, cytokine signal transduction in umbilical cord CD8+ T cells and downstream effects on CD8+ T cell function and repertoire in PT infants. We hypothesize that inflammatory mediators present in clinical chorioamnionitis disrupt normal fetal T cell homeostasis, resulting in expansion of CD8+ T cells that are functionally dysregulated and less diverse. This finding would have two important consequences on the preterm host immune system: 1) The immune system becomes dominated by CD8+ T cells that are hyper-responsive and potentiate inflammation, and 2) Compromised CD8+ T cell receptor repertoire that leaves them less able to mount protective immune responses to pathogen. The immediate goal of our project is to characterize the interaction between extrinsic environmental factors and intrinsic developmentally regulated mechanisms of CD8+ T cell activation. My long-term goal is to exploit these mechanisms pharmacologically to enhance or attenuate CD8+ T cell responses in PT infants, thereby improving their outcomes. To achieve our goals, we will interrogate cytokine pathways associated with CD8+ T cell activation and differentiation. We will characterize, by V? CDR3 mRNA sequencing, the CD8+ TCR repertoire diversity in PT infant cord blood and the degree to which it is compromised by in utero infections. We will identify from within an existing longitudinal study cohort a set of subjects born d 32 weeks gestation, and full term controls, with and without infection. Comparisons of CD8+ T cell phenotype, cytokine signal transduction, plasma cytokine concentrations and TCR diversity index will be made between cases and controls to reveal the relative contributions of development and environmental changes on CD8+ T cell development. The overall K08 application is designed to build a foundation of technical, intellectual and leadership skills required to transition into independence. The career development plan includes didactics to strengthen my knowledge base in T cell biology and fetal development, grant writing and immune modeling. I have selected scientific and career development seminars that I will attend regularly, and national meetings in order to identify novel research directions and increase recognition of my work in the larger field of neonatal immunology. My experienced mentors and advisory committee will monitor adherence to the detailed three- year productivity and developmental progress timeline. Invested mentorship, support for conducting translational science, depth of T cell immunology expertise and equipment, and a collaborative environment at the University of Rochester will provide the necessary tools with which I can build my early career.

描述（由申请人提供）：早产儿（早产儿，PT）非常容易受到病毒感染，这引发了有关其 CD8+ T 细胞功能的问题。脐带血 来自 PT 婴儿的 CD8+ T 细胞活化程度更高，并且对体外炎症刺激反应过度。本提案的目的是研究与子宫内感染相关的细胞因子环境异常、脐带 CD8+ T 细胞中的细胞因子信号转导以及对 PT 婴儿 CD8+ T 细胞功能和库的下游影响。我们假设临床绒毛膜羊膜炎中存在的炎症介质破坏了正常的胎儿 T 细胞稳态，导致功能失调且多样性较低的 CD8+ T 细胞扩增。这一发现将对早产宿主免疫系统产生两个重要影响：1) 免疫系统由反应过度并加剧炎症的 CD8+ T 细胞主导，2) CD8+ T 细胞受体库受损，使其无法安装对病原体的保护性免疫反应。我们项目的直接目标是表征外在环境因素与 CD8+ T 细胞激活的内在发育调节机制之间的相互作用。我的长期目标是从药理学角度利用这些机制来增强或减弱 PT 婴儿的 CD8+ T 细胞反应，从而改善其结果。为了实现我们的目标，我们将探究与 CD8+ T 细胞激活和分化相关的细胞因子途径。我们将用V？ CDR3 mRNA 测序、PT 婴儿脐带血中 CD8+ TCR 库的多样性及其受子宫内感染影响的程度。我们将从现有的纵向研究队列中确定一组妊娠 32 周出生的受试者，以及足月对照，无论是否感染。将在病例和对照之间比较CD8+ T细胞表型、细胞因子信号转导、血浆细胞因子浓度和TCR多样性指数，以揭示发育和环境变化对CD8+ T细胞发育的相对贡献。整个 K08 申请旨在为过渡到独立所需的技术、智力和领导技能奠定基础。职业发展计划包括加强我在 T 细胞生物学和胎儿发育、资助写作和免疫建模方面的知识基础的教学。我选择了定期参加的科学和职业发展研讨会以及全国会议，以确定新的研究方向并提高我在新生儿免疫学更大领域的工作的认可度。我经验丰富的导师和咨询委员会将监督对详细的三年生产力和发展进度时间表的遵守情况。罗切斯特大学的投资指导、对开展转化科学的支持、深度的 T 细胞免疫学专业知识和设备以及协作环境将为我建立早期职业生涯提供必要的工具。