Research - Laboratory/Non-Laboratory, Staff/Administrative
About the Job:
A unique exciting opportunity for NIH-funded Researcher 6 position is available in the laboratory of Bradley J. Segura, MD, PhD to work on Molecular Neuroscience & Immunology projects within the Department of Surgery (DOS) at the University of Minnesota. The Segura laboratory has begun a multi-year project to characterize the role of the Enteric Nervous System in pediatric intestinal disease.
Necrotizing enterocolitis (NEC) is a devastating problem for a rising population of premature infants, affecting 0.1% of all newborn children and 7% of very low birth weight infants in the U.S. Traditional medical therapy often fails and affected patients frequently warrant surgical intervention, yielding a mortality approaching 50% and a host of other long-term complications in survivors. Particular vulnerability of the intestinal tract in premature infants appears to be an important factor in the development of NEC. Nonetheless, the underlying mechanisms in the etiology of NEC remain insufficiently understood. The enteric nervous system (ENS) governs multiple aspects of intestinal function and may also be integral in mediating intestinal inflammation, yet a definitive role has not been established.
Our long term goal is to understand the role of the ENS in intestinal disease in children and to characterize its potential for preventive and therapeutic purposes. Within the ENS, enteric glia far outnumber neurons and demonstrate substantial signaling diversity. Work in our laboratory has characterized signaling events mediated by the bioactive lipid signaling molecule sphingosine-1-phosphate (S1P) in enteric glia—a pathway that has been shown to be integral to inflammatory pathways in other models. Previously, a putative role for enteric glia in intestinal inflammation prevention was suggested by another group of investigators when their selective ablation in mice led to fulminant intestinal disease (Bush et al, Cell 1998). Acknowledging limitations in this initial landmark study, it nonetheless served as an impetus for studies that followed. Research by our lab and others continues to unveil the increasing importance of these cells that were initially felt to merely serve as passive elements in the intestine. The objective of this proposal is to further elucidate the protective signaling mechanisms of glial cells of the ENS and their relevance in pediatric intestinal disorders of inflammation such as NEC.
Based on our preliminary data and relevant work in the CNS, we believe that a relationship exists between S1P signaling and inflammation within the ENS. Our central working hypothesis is that enteric glia are essential for the establishment of normal gut barrier function in children and this homeostatic balance is undeveloped in premature infants which may predispose them to NEC. Further, bioactive lipid signaling appears to protect against intestinal inflammation. Our studies demonstrate that enteric glia bear receptors for S1P and these receptors couple to downstream cellular events which may prove integral to the maintenance of gut barrier integrity in children with a developmentally mature enteric nervous system.
We plan to test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following Specific Aims:
1. Demonstrate enteric glial cell signaling contributes to normal gut barrier function in children.
We will test the hypothesis that developmental maturity allows enteric glial cell participation in normal intestinal epithelial barrier establishment. We will investigate the role of S1P and related growth factors in the maintenance of normal gut barrier function in vitro and in vivo.
2. Establish that enteric glial signaling is undeveloped in children with necrotizing enterocolitis, contributing to disrupted gut barrier function.
We will test the hypothesis that premature infants are at greater risk of acquiring NEC due to an immature ENS and paucity of enteric glia. We will investigate the involved signaling mechanisms in an established model of NEC. To further expand in a translational effort, we additionally plan to correlate these observations with clinical findings in human patients with NEC.
The studies proposed in these two chief aims are expected to identify mechanisms by which glial cells of the enteric nervous system protect against intestinal inflammation in children. We anticipate this work will have an important positive impact on the treatment and potential prevention of childhood intestinal inflammatory disorders including NEC by uncovering means by which these enigmatic cells and their involved signaling pathways may serve as targets for therapy.
We are now seeking highly motivated individuals who have knowledge and expertise relevant to the respective in vitro and in vivo projects. Successful candidates working in Dr. Segura’s laboratory in the DOS will have access to the University of Minnesota's state-of-the-art facilities and resources. Specific duties include:
• Daily independent management and coordination of project goals; report progress to the PI weekly • Develop and optimize experimentation in collaboration with and under the guidance of the PI • Analyze complex data and interpret test results • Prepare manuscripts and grants in collaboration with and under the guidance of the PI • Present findings at scientific conferences (posters and presentations) • Train lab personnel on specialized techniques; supervise and evaluate performance • Oversee project financial management and budgeting under the guidance of the PI
• Advanced degree with substantial research and publication record in related area • Proven molecular biology skills with additional experience with cell culture, transfection, cell proliferation assays, flow cytometry and fluorescent microscopy. • Experience with animal experiments, microdissection, transgenic mouse colonies. • Experience with complex data analysis and interpretation. • Experience in supervising and training other laboratory personnel in specialized techniques • Experience presenting results at scientific conferences [posters and talks]. • Proven ability to write scientific papers and achieve publication in internationally refereed journals. • Proven ability to independently coordinate research projects.
• Interest, expertise and knowledge in neuroscience/neuroimmunology. • Ability to work collaboratively with a diverse group of research scientists with different skill sets and expertise. Must be a team player. • Experience with independently mentoring and training undergraduates, graduate students or medical residents.
Internal Number: 340792
About University of Minnesota, Twin Cities
The University of Minnesota, founded in the belief that all people are enriched by understanding, is dedicated to the advancement of learning and the search for truth; to the sharing of this knowledge through education for a diverse community; and to the application of this knowledge to benefit the people of the state, the nation, and the world.