Research Interests
Homeostasis and disease at the Maternal Fetal Interface:
Over the past five years, preterm birth (PTB) (<37 weeks’ gestation) has been the leading cause of death worldwide. In 2016, almost ten percent of all infants born in the United States were delivered prematurely, and by 2018 the United States was reported to have the most adverse outcomes during childbirth in the developed world. Collectively, PTB is estimated to cost $14 billion annually. Historically, PTB has been challenging to study as the underlying causes are poorly understood, and there is a lack of physiologically relevant animal models.
Using multi-omic analysis, we have recently shown that placental villi contain numerous immune cells beyond classical Hoffbauer cells (Toothaker et al., Development, 2022). Building on these multiomic suspension and spatial techniques, we are developing an atlas of placental development across gestation in healthy pregnancies and disease states.
Furthermore, our recently published work was the first to document the contribution of immune cells within the placental villi (PV) to intraamniotic inflammation in non- human primates and specifically uncovered that PV T cells are active and inflammatory in this model (Toothaker et al., Front In Imm, 2020). We hypothesize that failed restriction of antigen presentation to PV T cells leads to PV T cell overactivation, increased cytokine production, and subsequent destruction of placental architecture resulting in PTB. Our NIH funded work uses multi-omic analysis coupled with in vitro functional assays on preterm and term placentas to uncover unique PV T cells populations, functional capacity, transcriptional machinery, and downstream responses on trophoblasts in preterm birth. At its completion, this study will increase our understanding of the function of T cells in pregnancy and in other immunological tolerance settings.
Using multi-omic analysis, we have recently shown that placental villi contain numerous immune cells beyond classical Hoffbauer cells (Toothaker et al., Development, 2022). Building on these multiomic suspension and spatial techniques, we are developing an atlas of placental development across gestation in healthy pregnancies and disease states.
Furthermore, our recently published work was the first to document the contribution of immune cells within the placental villi (PV) to intraamniotic inflammation in non- human primates and specifically uncovered that PV T cells are active and inflammatory in this model (Toothaker et al., Front In Imm, 2020). We hypothesize that failed restriction of antigen presentation to PV T cells leads to PV T cell overactivation, increased cytokine production, and subsequent destruction of placental architecture resulting in PTB. Our NIH funded work uses multi-omic analysis coupled with in vitro functional assays on preterm and term placentas to uncover unique PV T cells populations, functional capacity, transcriptional machinery, and downstream responses on trophoblasts in preterm birth. At its completion, this study will increase our understanding of the function of T cells in pregnancy and in other immunological tolerance settings.
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Mucosal Immunity in health and disease:
Using cutting edge techniques such as mass cytometry (CyTOF) and single cell RNA sequencing (scRNAseq), spatial transcriptomics and imaging mass cytometry, our group is currently focused on studying how mucosal immunity develops and what goes awry to cause disease.
One of the main focuses of our group is to understand how mucosal homeostasis develops in infants and young children, particularly as it relates to development and maintenance of adaptive immunity. Using a combination of single cell techniques and organoid models, we are studying intestinal immunity of fetal, premature and term infants and pediatric subjects. As part of our studies related to development of mucosal immunity, we are also interested in identifying factors such as bacterial metabolites and byproducts that are involved in establishing and maintaining a healthy mucosal immune system (Li et al., JCI Insight, 2020).
Furthermore, we are interested in determining how mucosal homeostasis becomes dysregulated in intestinal diseases such as necrotizing enterocolitis (NEC), spontaneous ileal perforation (SIP), and inflammatory bowel disease (IBD).
One of the main focuses of our group is to understand how mucosal homeostasis develops in infants and young children, particularly as it relates to development and maintenance of adaptive immunity. Using a combination of single cell techniques and organoid models, we are studying intestinal immunity of fetal, premature and term infants and pediatric subjects. As part of our studies related to development of mucosal immunity, we are also interested in identifying factors such as bacterial metabolites and byproducts that are involved in establishing and maintaining a healthy mucosal immune system (Li et al., JCI Insight, 2020).
Furthermore, we are interested in determining how mucosal homeostasis becomes dysregulated in intestinal diseases such as necrotizing enterocolitis (NEC), spontaneous ileal perforation (SIP), and inflammatory bowel disease (IBD).
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Intestinal Health:
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Using small intestinal organoids derived from tissue across the human lifespan (fetal to adult) we aim to understand the effect of various environmental factors such as diet, metabolites, drugs, and microbiome on intestinal health through monitoring epithelial growth and differentiation.
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Drivers of immune development and regulation in infancy:
Very little is known about function of the fetal immune system and its unique properties associated with gestation and early life. Historically, fetal immune system was thought to be immature. However recent findings from our group and others demonstrate that adaptive immunity (particularly memory T cells) is establishment prior to the third trimester of pregnancy (Stras et al., Developmental Cell, 2019) and are driving a paradigm shift in our understanding of neonatal immune function. Given the unique requirements associated with gestation (i.e., balancing tolerance and development of protective immunity) in preparation for birth, it is likely that the function of the fetal immune system differs from that of adult immunity. As such, unique susceptibilities of early life might be due to specific mechanisms evolved to protect the offspring during the critical window of transition to ex utero life rather than secondary to immune immaturity. However, very few studies have systematically addressed how early life peripheral immune system develops, when it transitions to more adult-like states, and how early trajectories shape later immune set point establishment. We have been able to overcome the limitations of studying these vulnerable populations by optimizing multiomic analysis on microsamples and with the help of the NOuRISH team (https://medicine.yale.edu/pediatrics/sections/neonatal-perinatal/research/nourish-program/) have established a longitudinal cohort of premature infants to answer these questions and characterize early immune development at unprecedented granularity. Moreover, we are collecting matched microbiome samples to define microbiome-host interactions involved in health and disease
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