This proposal describes a 4-year training program for the development of my academic career in Neonatal Medicine. I have completed formal residency in General Pediatrics and subspecialty fellowship training in Neonatal Medicine at the Children's Hospital of Philadelphia (CHOP). I am now expanding my scientific skills in developmental immunology and neonatal innate immunity and developing my clinical skills in taking care of preterm neonates and infants as an Assistant Professor of Pediatrics at Cincinnati Children's Hospital Medical Center (CCHMC). Dr. Jeffrey Whitsett, an accomplished neonatologist, renowned developmental biologist and a member of the Institute of Medicine (IOM) will mentor my scientific development. Dr. Whitsett is the Vice- Chair for Basic Science Research at CCHMC and has mentored more than 30 physician-scientists. Dr. Harinder Singh, an investigator with the Howard Hughes Medical Institute (HHMI) and an international authority in developmental immunology and dendritic cell biology will complement Dr. Whitsett. Dr. Singh has successfully mentored several junior faculty members and postdoctoral fellows. To further promote my scientific development, I have established a research advisory committee of highly regarded physician scientists consisting of Dr. Sing Sing Way and Dr. Scott Worthen. The proposed research focuses on the role of commensal bacteria in developmental regulation of innate immune responses to sepsis, the leading cause of death in neonates. I found that disruption of commensal bacteria by antibiotics suppressed postnatal neutrophil production and made the neonatal mice more susceptible to Escherichia coli (E. coli), the leading cause of neonatal sepsis. The cytokine, interleukin (IL) 17 is a major homeostatic mechanism for regulation of neutrophil production. I found that antibiotics decreased the number of IL-17 producing innate lymphoid cells (ILC) in the intestine. Reconstitution of commensal bacteria restored the number of IL-17 producing ILC, promoted postnatal neutrophil production and restored the neonate's resistance to E. coli. I now propose to dissect the immune signals by which commensal bacteria regulate neutrophil production and control neonatal resistance to infection.
In Aim 1, I will employ a combination of flow cytometry, bacterial reconstitution; transgenic mice to selective ablate immune cells and use adoptive transfer to identify the specific cells that detect commensal bacteria to regulate neonatal host defense.
In Aim 2, I will use a combination of ex vivo studies, gene targeted mice and antibody-mediated neutralization to determine how commensal bacteria cells interact with ILC to regulate postnatal neutrophil production and control neonatal host resistance. These studies will clarify the role of commensal bacteria in the developmental regulation of neutrophil number and explain why disruption of normal intestinal commensals results in increased risk of neonatal sepsis. This will lead to better probiotic, antibiotic, and pharmacologic strategies for immune support of the neonates and thus reduce the mortality and morbidity in this vulnerable population. CCHMC provides an ideal scientific environment for my training as a physician-scientist. I will take advantage of the intellectual strength and academic track record of my mentor and scientific advisory committee members, and the robust expertise and resources afforded at CCHMC to accomplish this proposed training program.
Sepsis is responsible for more than one million neonatal deaths around the world each year. Recent studies clearly demonstrate that disruption of intestinal commensal bacteria results in increased risk of neonatal sepsis. Neutrophils are critical mediators of innate immune response in neonatal sepsis but the role of commensal bacteria in neutrophil homeostasis is unclear. The proposed studies will clarify the role of commensal bacteria in regulation of neutrophil mediated host-defense. Uncovering the mechanism by which alteration of commensal bacteria contributes to neonatal sepsis will lead to new therapeutic approaches for immune support of neonates receiving antibiotics. This will help us devise better strategies to restore the normal commensal bacteria, which is altered by antibiotic use.
| Allen, Amil; Deshmukh, Hitesh (2017) All on ""CHIP"": using microfluidics to study neutrophil ontogeny. Transl Res 190:1-3 |
| Gray, Jerilyn; Oehrle, Katherine; Worthen, George et al. (2017) Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection. Sci Transl Med 9: |
| Taft, Diana H; Ambalavanan, Namasivayam; Schibler, Kurt R et al. (2015) Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants. PLoS One 10:e0130604 |
