Despite decades of research, there is a fundamental gap in our understanding of how to adequately protect the intestines from the sequellae of ischemia/reperfusion (I/R) injury. We have accumulated multiple lines of evidence demonstrating that heparin-binding EGF-like growth factor (HB-EGF) can protect the intestines from I/R injury. The long-term goal of our work is to administer HB-EGF therapeutically to protect the intestines from injury. The overall objective of the current renewal application is to identify key elements of the interaction of HB- EGF with stem cells (SC) that may be utilized to augment the activity of the growth factor. Our central hypothesis is that a significant proportion of the intestinal cytoprotective effects of HB- EGF are mediated through its effects on SC, and that the interaction of HB-EGF with SC can be augmented in order to increase the efficacy of the growth factor. The rationale is that once the interactions of HB-EGF with SC are better understood, maximally beneficial innovative approaches to the treatment of intestinal I/R injury can be developed. We will objectively test our central hypothesis by pursuing the following specific aims:
Aim 1) to determine the signaling mechanisms and receptors utilized by HB-EGF in protecting intestinal SC (ISC) from injury. We will use highly purified ISC to determine the effects of HB-EGF on the Wnt, BMP, PI3K and Notch signaling pathways in these cells.
Aim 2) to determine whether endogenous HB-EGF expression affects ISC expansion and differentiation after injury. We will use a novel ex vivo crypt-villous organoid culture system and an in vivo intestinal I/R injury model to investigate the effects of HB-EGF on ISC expansion and differentiation.
Aim 3) to determine whether bone marrow (BM)-derived SC can improve HB-EGF-mediated protection of the intestines from injury. We will determine the effects of SC mobilization or administration, in conjunction wth HB-EGF administration, in protection of the intestines from I/R injury in vivo. The results of our studies are expected to have an important positive impact in terms of providing improved therapeutic interventions for patients suffering from intestinal I/R injury, in addition to fundamentally advancing the understanding of growth factor/SC interactions in the intestines. This contribution is significant because it will enable us to best exploit the potential of clinical HB-EGF therapy. The proposed research is innovative because we seek to shift current experimental therapies for intestinal I/R injury away from the targeting of single inflammatory mediators, and towards strategies designed to protect and regenerate the intestinal mucosa, through administration of an intestinal cytoprotective growth factor in conjunction with multipotent SC.

Public Health Relevance

The proposed research is relevant to public health because it is expected to lead to a novel therapeutic strategy that will decrease morbidity and mortality related to intestinal I/R injury. The innovative approach to intestinal I/R injury that is proposed will lead to substantive improvements in clinical outcomes at the bedside, which is consistent with the mission of the NIH.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061193-11
Application #
8473683
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2002-01-15
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$300,424
Indirect Cost
$92,949
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Wei, Jia; Zhou, Yu; Besner, Gail E (2015) Heparin-binding EGF-like growth factor and enteric neural stem cell transplantation in the prevention of experimental necrotizing enterocolitis in mice. Pediatr Res 78:29-37
Besner, Gail E (2015) A pain in the NEC: research challenges and opportunities. J Pediatr Surg 50:23-9
Wei, Jia; Besner, Gail E (2015) M1 to M2 macrophage polarization in heparin-binding epidermal growth factor-like growth factor therapy for necrotizing enterocolitis. J Surg Res 197:126-38
Chen, Chun-Liang; Yang, Jixin; James, Iyore O A et al. (2014) Heparin-binding epidermal growth factor-like growth factor restores Wnt/β-catenin signaling in intestinal stem cells exposed to ischemia/reperfusion injury. Surgery 155:1069-80
Yang, Jixin; Su, Yanwei; Zhou, Yu et al. (2014) Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects. Pathophysiology 21:95-104
Watkins, Daniel J; Zhou, Yu; Matthews, Mika A B et al. (2014) HB-EGF augments the ability of mesenchymal stem cells to attenuate intestinal injury. J Pediatr Surg 49:938-44; discussion 944
Yang, Jixin; Su, Yanwei; Besner, Gail E (2014) Stem cell therapy for necrotizing enterocolitis: innovative techniques and procedures for pediatric translational research. Methods Mol Biol 1213:121-37
Su, Yanwei; Besner, Gail E (2014) Heparin-binding EGF-like growth factor (HB-EGF) promotes cell migration and adhesion via focal adhesion kinase. J Surg Res 189:222-31
Zhou, Yu; Yang, Jixin; Watkins, Daniel J et al. (2013) Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy. Stem Cell Res Ther 4:157
Watkins, Daniel J; Yang, Jixin; Matthews, Mika A B et al. (2013) Synergistic effects of HB-EGF and mesenchymal stem cells in a murine model of intestinal ischemia/reperfusion injury. J Pediatr Surg 48:1323-9

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