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ETC-EDNRB Signaling in Enterocolitis Associated with Colonic Aganglionosis

Investigators
Frykman, Philip Kent
Institutions
Cedars-Sinai Medical Center
Start date
2011
End date
2016
Objective
Children with aganglionic colon present with a constellation of symptoms (e.g., severe constipation, diarrhea, intestinal inflammation) that predispose to sepsis, and can be life-threatening. Surgical correction eradicates these symptoms in most cases. But in up to 30% of cases, surgery fails to cure the disorder, and thereafter, children suffer from chronic enterocolitis that can lead to bacteremia, outright sepsis, and even death. Almost nothing is known about the underlying mechanisms of this postoperative enterocolitis. As a means to pursue mechanistic studies, we created an animal model of postoperative enterocolitis associated with aganglionosis using the Endothelin Receptor B-null mouse with colonic aganglionosis.

We developed a novel microsurgical procedure that is essentially identical to the operation performed clinically, and essentially cures aganglionic megacolon in Ednrb-/- mice, just as it does in human patients. We found that a significant proportion of Ednrb- /- mice develop postoperative enterocolitis despite satisfactory surgical outcome, similar to what occurs clinically in human patients. In the course of our studies, we serendipitously discovered a spectrum of striking immune abnormalities in Ednrb-/- mice. These abnormalities occur at or shortly after birth, appear to worsen with age, and include reduced spleen size, reduced absolute numbers of lymphocytes in the spleen, marked reduction in marginal zone B cells and B cell/T cell ratio in the spleen, thymic involution, and bone marrow abnormalities. Upon examination of mice with a genetic lack of entdothelin-3 (ET3; the preferred ligand for the Ednrb receptor), we found very similar immune abnormalities.

Our preliminary studies thus far are consistent with the interpretation that ET3 signaling through Ednrb is required for normal development of the immune system, and/or for normal function of the immune system in the adult animal. We therefore propose that 1) ET3/Ednrb signaling is essential for normal development of the immune system; 2) when disrupted, two distinct phenotypic features emerge: colonic aganglionosis, with a marked propensity to develop enterocolities even after successful surgical correction, and an immune system that displays marked structural and functional abnormalities. We suspect that these two phenotypic features are indeed related to one another, and our ultimate goal is to understand and describe in molecular and cellular terms the precise basis of the interrelationships.

This application proposes an a detailed, comprehensive training plan that will allow the applicant to pursue immunologic studies related to disrupted ET3/Ednrb signaling. An outstanding team of Mentors will directly oversee the research training and the all aspects of the investigation. The ultimate goal is for the applicant to leverage the data obtained during this proposed investigation into a successful R01 application. This will then allow the applicant to become an independently-funded surgeon-scientist investigating the role of specific signaling pathways and genes in immune development and function, and how these are linked to colonic ganglionosis and the associated enterocolitis that occurs in these diseases.

More information
Public Health Relevance: We developed an animal model of enterocolitis associated with aganglionosis using the Endothelin Receptor B-null mouse with colonic aganglionosis that closely mimics the features of the human condition. During our studies, we made a critical new observation that the Ednrb-null mice also had lymphopenia-albeit as yet undescribed-role in development of enterocolitis. Our novel findings suggest that ET3-Ednrb signaling plays a critical role for normal immune system development in mice, which forms the basis of this proposal. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers' commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.
Funding Source
Nat'l. Inst. of Diabetes and Digestive and Kidney Diseases
Project source
View this project
Project number
1K08DK090281-01
Categories
Sanitation and Quality Standards
Chemical Contaminants
Heavy Metals
Parasites
Bacterial Pathogens