LAY ABSTRACT A small but significant percentage of children are born with severe life threatening diarrhea that can be classified as congenital. These children frequently have one of a growing group of genetic disorders that generally result in improper movement of various nutrients and salts across the intestine. We have recently discovered that a group of children who are incapable to absorbing all forms of nutrients have a genetic disorder that results in the inability to form enteroendocrine cells. Enteroendocrine cells are the hormone producing cells that reside in the gut and their formation is driven by a gene named Neurogenin3 that is defective in these children. In this grant application, we propose to identify more children with defects in the NEUROGENIN-3 gene so that we can get a better understanding of the clinical implications of this disorder. We also have been working on mice that carry a similar mutation of the NEUROGENIN-3 gene and we're using it to isolate the early and late forms of enteroendocrine cells in mice and humans. One main goal is to isolate these cells is so that we can get a better understanding of how they work, and how subsets of these cells develop. We have also found that NEUROGENIN-3 causes enteroendocrine cells that are grown in the laboratory to stop dividing and to take on the characteristics of mature enteroendocrine cells. We hope to understand the mechanism of how NEUROGENIN-3 causes the cells to stop dividing and to determine if a similar process is occurring in live mice. Finally, we have evidence that a loss of enteroendocrine cells results in a dysfunction of the intestinal cells called enterocytes that are responsible for absorbing nutrients. Here we plan a series of experiments to begin understanding the mechanism of how an absence of enteroendocrine cells leads to improper handling of nutrients by the enterocytes.
Children that develop chronic diarrhea shortly after birth have a very high mortality rate and these conditions are not well understood. We have recently discovered a new disorder that results in congenital diarrhea that occurs from the failure to develop gut hormone producing cells. In this grant we propose experiments to examine this group of humans and mice (with an identical condition) more closely. At the completion of these aims, we anticipate having further analyzed the physiologic basis of this disorder and will have further elucidated the mechanism of how the gene that is defective in this disorder (NEUROGENIN-3) causes gut endocrine cells to develop and function. We believe that these studies will provide new strategies of how to improve nutrient absorption in these patients and to understand this process more fully in health.
|Rouch, Joshua D; Scott, Andrew; Lei, Nan Ye et al. (2016) Development of Functional Microfold (M) Cells from Intestinal Stem Cells in Primary Human Enteroids. PLoS One 11:e0148216|
|Canani, Roberto Berni; Castaldo, Giuseppe; Bacchetta, Rosa et al. (2015) Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol 12:293-302|
|Wilschanski, Michael; Abbasi, Montaser; Blanco, Elias et al. (2014) A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity. PLoS One 9:e108878|
|Blanco, Elias H; Peinado, Juan R; MartÃn, MartÃn G et al. (2014) Biochemical and cell biological properties of the human prohormone convertase 1/3 Ser357Gly mutation: a PC1/3 hypermorph. Endocrinology 155:3434-47|
|Lei, Nan Ye; Jabaji, Ziyad; Wang, Jiafang et al. (2014) Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 9:e84651|
|Jabaji, Ziyad; Brinkley, Garrett J; Khalil, Hassan A et al. (2014) Type I collagen as an extracellular matrix for the in vitro growth of human small intestinal epithelium. PLoS One 9:e107814|
|MartÃn, MartÃn G; Lindberg, Iris; Solorzano-Vargas, R Sergio et al. (2013) Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology 145:138-48|
|Yourshaw, Michael; Solorzano-Vargas, R Sergio; Pickett, Lindsay A et al. (2013) Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. J Pediatr Gastroenterol Nutr 57:759-67|
|Kanji, Murtaza S; Martin, Martin G; Bhushan, Anil (2013) Dicer1 is required to repress neuronal fate during endocrine cell maturation. Diabetes 62:1602-11|
|Pickett, Lindsay A; Yourshaw, Michael; Albornoz, Valeria et al. (2013) Functional consequences of a novel variant of PCSK1. PLoS One 8:e55065|
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