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. Amlie 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 Passegu. 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.
Neonatal sepsis causes significant morbidity and mortality worldwide, thought to be due in part to a developing blood system that does not mount an appropriate neutrophilic response to infection. Adult hematopoietic stem and progenitor cells (HSPCs) sit at the top of the hematopoietic hierarchy and rapidly respond to inflammatory signals to repopulate all lineages of blood cells, including neutrophils, but how those cells function during the fetal and neonatal period is not well understood. This proposal seek to define the ability of fetal and neonatal HSPCs to respond to inflammation, paving the way for better treatment of neonatal infections and sepsis.
