Mapping the unique features of fetal and neonatal hematopoietic stem and progenitor cells conferring susceptibility to inflammation and infection

项目总结 新生儿败血症是一个重大的全球健康负担，每年有140万新生儿死亡，许多 更多的人由于炎症和感染而出现严重的终生健康问题。新生儿是 唯一易患败血症的，部分原因是免疫反应不能充分控制入侵 病原体。特别是，新生儿对感染的反应的显著中性粒细胞减少的特征是一个主要的 新生儿死亡率的贡献者，这种情况在成年人中很少发生。成人造血干细胞(HSCs)位于 在造血层次的顶端，产生包括中性粒细胞在内的血液系统的所有谱系，以及 对炎症信号作出反应，根据需要再生血液系统。这是实现的 通过动态产生具有不同基线的不同多能祖细胞(MPP)子集 倾向于某些血细胞谱系，但实质上具有可塑性，因此它们的相对频率 而炎性信号改变了血统潜力。胎儿和新生儿的HSCs是否会导致类似的 MPP亚群，以及这些围产期MPP亚群是否对炎症做出反应以重建血液系统 与成年人口的情况相同，目前尚不清楚。这是我们对围产期认识上的一个根本差距。 严重影响我们诊断和治疗新生儿败血症的造血功能。这项建议 代表一项为期四年的职业发展计划，旨在通过两种重要方式填补这一缺口。第一，研究 本应用中提出的策略将建立围产期HSC/MPP生物学的全面路线图 使用小鼠模型作为未来分析人类HSC/MPP群体的模板进行翻译研究。 在特定的目标1中，我们将通过体外和体外试验来评估胎儿和新生儿的HSC/MPP功能。 体内移植方法，以评估其血统贡献和再生潜力，并使用 无偏向RNA-seq转录图谱研究其功能调控的分子机制 在不受干扰的发展过程中。在具体目标2中，我们将确定围产期HSC/MPPS的能力 通过解剖个体对炎症和感染的反应来建立对炎症和感染的紧急造血反应 IL-1、IL-6、IFNA和TNFa等关键炎性细胞因子与脂多糖和群毒素体内模型的应用 B型链球菌(GBS)绒毛膜羊膜炎和早发性败血症。二、职业发展与培训 这项提案中概述的活动将使国际和平研究所阿梅利·柯林斯博士进行终身独立研究 研究围产期造血的独特特性如何导致新生儿发病率和 死亡率。柯林斯博士是哥伦比亚大学欧文分校的新生儿专家和儿科学助理教授 医学中心，在免疫学和人类新生儿状况方面有重要的背景。她将补充 在他的指导下，在发育造血和干细胞生物学方面的培训方面的专业知识。 伊曼纽尔·帕塞古。在完成这项K08之后，柯林斯博士将准备承担她自己的监督工作 旨在通过对围产期造血的新见解来促进新生儿健康的研究计划。

PROJECT SUMMARY Neonatal sepsis is a significant global health burden, with 1.4 million newborns dying annually and many more with substantial lifelong health problems as a consequence of inflammation and infection. Neonates are uniquely susceptible to sepsis in part due to an immune response that fails to adequately control invading pathogens. In particular, the marked neutropenia characteristic of the neonatal response to infection is a primary contributor to mortality in newborns that rarely occurs in adults. Adult hematopoietic stem cells (HSCs) sit at the top of the hematopoietic hierarchy, giving rise to all lineages of the blood system including neutrophils, and responding to inflammatory signals to regenerate the blood system according to demand. This is achieved through the dynamic production of different multipotent progenitor (MPP) subsets with distinct baseline predispositions toward certain lineages of blood cells but substantial plasticity such that their relative frequency and lineage potentiality is modified by inflammatory signals. Whether fetal and neonatal HSCs give rise to similar MPP subsets, and whether these perinatal MPP subsets respond to inflammation to rebuild the blood system in the same way as adult populations is not known. This is a fundamental gap in our understanding of perinatal hematopoiesis that significantly impairs our ability to diagnose and treat neonatal sepsis. This proposal represents a four year career development plan aimed at filling that gap in two important ways. First, the research strategy proposed in this application will establish a comprehensive roadmap of perinatal HSC/MPP biology using mouse models as a template for future analyses of human HSC/MPP populations for translational studies. In Specific Aim 1, we will evaluate HSC/MPP function in the fetus and neonate through in vitro assays and in vivo transplantation approaches to assess their lineage contributions and regenerative potential, and use unbiased RNA-seq transcriptomic profiling to investigate the molecular mechanisms regulating their function during unperturbed development. In Specific Aim 2, we will determine the ability of perinatal HSC/MPPs to mount an emergency myelopoietic response to inflammation and infection by dissecting individual responses to key inflammatory cytokines such as IL-1, IL-6, IFNa, and TNFa and employing in vivo models of LPS and Group B Streptococcus (GBS) chorioamnionitis and early onset sepsis. Second, the career development and training activities outlined in this proposal will position the PI, Dr. Amélie Collins, for a life-long independent research career investigating how the unique properties of perinatal hematopoiesis contribute to neonatal morbidities and mortality. Dr. Collins is a neonatologist and Assistant Professor of Pediatrics at Columbia University Irving Medical Center with significant background in immunology and human neonatal conditions. She will complement that expertise with training in developmental hematopoiesis and stem cell biology under the mentorship of Dr. Emmanuelle Passegué. Upon completion of this K08, Dr. Collins will be ready to assume oversight of her own research program aimed at advancing neonatal health through new insights into perinatal hematopoiesis.