I am a passionate physician scientist working in the Neonatal Intensive Care Unit and studying the neonatal immune system and the immunologic adaptations of pregnancy.
Born in Colorado, I have lived all over the country. I came to Stanford for fellowship in Neonatal-Perinatal Medicine after completing Pediatric Residency at the University of Michigan, and I stayed on as faculty after completing fellowship. I received my M.D. from Vanderbilt University School of Medicine and my Bachelor of Science from Brown University.
Instructor, Pediatrics - Neonatal and Developmental Medicine
Current Research and Scholarly Interests
I am a Neonatal Intensive Care physician scientist interested in the neonatal immune system, particularly the immune system of premature infants, and how it impacts the short and longterm health of this vulnerable population.
Dysregulated inflammation is at the heart of so many of the diseases suffered by our patients in the NICU. Diseases such as sepsis and necrotizing enterocolitis often afflict our babies in the first few weeks of life, while other inflammatory diseases, such as bronchopulmonary dysplasia and retinopathy of prematurity, affect patients for life. It is also likely that a dysregulated immune system is a major factor in the pathogenesis of the long-term neurodevelopmental impairment suffered by patients who were born premature.
In my current work, I use mass cytometry (CyTOF) to study the immune system and its behavior of premature infants. By using CyTOF, in combination with machine learning and other advanced statistical techniques, I am able to describe the neonatal immune system in great detail. I am particularly interested in how the profile of the neonatal immune system changes with gestational age, how it evolves over the course of the infant's first days and weeks of life, and how it relates to establishment of the gut microbiome.
Another area of focus is on immunology of human pregnancy. Pregnancy requires unique and remarkable immune adaptations in order to allow the mother to tolerate her semi-allogeneic fetus up until the time of delivery. Derangements in these immune adaptations are implicated in prematurity as well as diseases of pregnancy such as preeclampsia and intrauterine growth restriction, which are major indications for preterm delivery.
Multi-Omic, Longitudinal Profile of Third-Trimester Pregnancies Identifies a Molecular Switch That Predicts the Onset of Labor.
SPRINGER HEIDELBERG. 2020: 89A
View details for Web of Science ID 000525432600082
Outcomes and Resource Use Among Overweight and Obese Children With Sepsis in the Pediatric Intensive Care Unit.
Journal of intensive care medicine
2020; 35 (5): 472–77
To evaluate the effect of overweight and obesity on outcomes and resource use among patients with sepsis in the pediatric intensive care unit (PICU).Retrospective analysis of clinical characteristics, resource use, and mortality among children 0 to 20 years of age admitted to the C.S. MottChildren's Hospital PICU (University of Michigan) between January 2009 and December 2015, with a diagnostic code for sepsis at admission (based on International Classification of Diseases, Ninth Revision-Clinical Modification codes) and with weight and height measurements at PICU admission.A total of 454 participants met the inclusion criteria. Seventy-six were categorized as underweight (body mass index [BMI] percentile <5th) and were excluded, which left a final sample size of 378 participants. Children with a BMI >5th and <85th percentiles for age were categorized as normal weight and those with a BMI >85th percentile as overweight/obese. After descriptive and bivariate analyses, multivariate regression methods were used to assess the independent effect of obesity status on mortality and the use of PICU technology after adjustment for patient age and illness severity at admission. Of the 378 patients studied, 41.3% were overweight/obese. There was no difference in microbiologic etiology of sepsis (P = .36), median PICU length of stay in days (5.4 vs 5.6; P = .61), or PICU mortality (6.4% vs 7.2%; P = .76) by weight status. The use of specialized PICU technology including extracorporeal membrane oxygenation (odds ratio [OR]: 2.77, 95% confidence interval [CI]:1.13-6.79) and continuous renal replacement therapy (OR: 4.58, 95% CI: 1.16-18.0) was higher among overweight/obese patients, compared with normal weight patients.Although PICU mortality and length of stay were similar for obese-overweight patients and normal weight critically ill children with sepsis, there was significantly higher use of specialized organ-supportive technology among obese patients, likely indicating higher occurrence of multiple organ dysfunction.
View details for DOI 10.1177/0885066618760541
View details for PubMedID 29471722
View details for PubMedCentralID PMC6027613
Multiomic immune clockworks of pregnancy.
Seminars in immunopathology
Preterm birth is the leading cause of mortality in children under the age of five worldwide. Despite major efforts, we still lack the ability to accurately predict and effectively prevent preterm birth. While multiple factors contribute to preterm labor, dysregulations of immunological adaptations required for the maintenance of a healthy pregnancy is at its pathophysiological core. Consequently, a precise understanding of these chronologically paced immune adaptations and of the biological pacemakers that synchronize the pregnancy "immune clock" is a critical first step towards identifying deviations that are hallmarks of peterm birth. Here, we will review key elements of the fetal, placental, and maternal pacemakers that program the immune clock of pregnancy. We will then emphasize multiomic studies that enable a more integrated view of pregnancy-related immune adaptations. Such multiomic assessments can strengthen the biological plausibility of immunological findings and increase the power of biological signatures predictive of preterm birth.
View details for DOI 10.1007/s00281-019-00772-1
View details for PubMedID 32020337
VoPo leverages cellular heterogeneity for predictive modeling of single-cell data.
2020; 11 (1): 3738
High-throughput single-cell analysis technologies produce an abundance of data that is critical for profiling the heterogeneity of cellular systems. We introduce VoPo (https://github.com/stanleyn/VoPo), a machine learning algorithm for predictive modeling and comprehensive visualization of the heterogeneity captured in large single-cell datasets. In three mass cytometry datasets, with the largest measuring hundreds of millions of cells over hundreds of samples, VoPo defines phenotypically and functionally homogeneous cell populations. VoPo further outperforms state-of-the-art machine learning algorithms in classification tasks, and identified immune-correlates of clinically-relevant parameters.
View details for DOI 10.1038/s41467-020-17569-8
View details for PubMedID 32719375
- Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia FRONTIERS IN IMMUNOLOGY 2019; 10
Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
2019; 34 (12): 2042–50
Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1).Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later.GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice.These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
View details for DOI 10.1093/ndt/gfz050
View details for PubMedID 31071225
View details for PubMedCentralID PMC6887698
Human metapneumovirus small hydrophobic (SH) protein downregulates type I IFN pathway signaling by affecting STAT1 expression and phosphorylation.
2016; 494: 248–56
Type I interferon (IFN) is a key mediator of antiviral immunity. Human metapneumovirus (HMPV) inhibits IFN signaling, but does not encode homologues of known IFN antagonists. We tested the hypothesis that a specific viral protein prevents type I IFN signaling by targeting signal transducer and activator of transcription-1 (STAT1). We found that human airway epithelial cells (capable of expressing IFNs) became impaired for STAT1 phosphorylation even without direct infection due to intrinsic negative feedback. HMPV-infected Vero cells (incapable of expressing IFN) displayed lower STAT1 expression and impaired STAT1 phosphorylation in response to type I IFN treatment compared to mock-infected cells. Transient overexpression of HMPV small hydrophobic (SH) protein significantly inhibited STAT1 phosphorylation and signaling, and recombinant virus lacking SH protein was unable to inhibit STAT1 phosphorylation. Our results indicate a role for the SH protein of HMPV in the downregulation of type I IFN signaling through the targeting of STAT1.
View details for DOI 10.1016/j.virol.2016.04.022
View details for PubMedID 27131212
View details for PubMedCentralID PMC4930656
Effectiveness of a School-Based Deworming Campaign in Rural Kenya
JOURNAL OF TROPICAL PEDIATRICS
2011; 57 (6): 461-463
In 2007, the rate of intestinal helminth infection in primary school-aged children in a rural village in Southwestern Kenya was estimated to be at least 68%, based on direct stool smear. Since the 2007 survey, these same school children have been treated with 400-mg albendazole every 3 months. We repeated a cross-sectional stool survey in the same area in 2010 (i.e. 3 years later) to estimate the current parasite prevalence. While only 44.5% of children were infected in 2010, the decline was not as marked as one might expect from a well-managed quarterly deworming campaign. Due to the relative insensitivity of the technique utilized here-the direct smear examination of a single stool sample-we were only able to identify heavy infections, and the true rate of parasitism is likely much higher, suggesting heavy environmental contamination and rapid re-infection rates. Community education and sanitation improvements are needed for more definitive impact.
View details for DOI 10.1093/tropej/fmq118
View details for Web of Science ID 000297574000011
View details for PubMedID 21212131