Defective intestinal transport is a central component of many intestinal diseases. Such transport, in the form of nutrient, ion, and water absorption, is accomplished by specific transcellular transporters as well as passive paracellular movement across the epithelial tight junction. An emerging view is that individual transporters can regulate one another as well as paracellular permeability, resulting in coordinate regulation of intestinal transport. This concept is supported by our studies of Na+-glucose cotransport-dependent tight junction regulation showing that SGLT1, the apical Na+-glucose cotransporter, activates a signal transduction cascade that sequentially triggers delivery of NHE3, an apical Na+-H+ exchanger, to the plasma membrane, increased apical Na+-H+ exchange, myosin light chain (MLC) kinase activation, MLC phosphorylation, actomyosin contraction, and increased tight junction permeability. Despite these and other advances, the mechanisms by which vesicular transport, protein interactions, and actomyosin contraction effect regulation of intestinal epithelial transport and barrier function remain largely undefined. This critical gap limits our ability to understand the mechanisms of diseases with intestinal transport and barrier dysfunction, including infectious, inflammatory, and malabsorptive diarrheal diseases. Thus, the objectives of this application are to define the mechanisms by which signal transduction pathways that activate membrane traffic and modify protein interactions are involved in regulation of intestinal transport and barrier function. We will accomplish these objectives through three specific aims: 1. To define the role of ezrin in acute regulation of protein delivery to the plasma membrane, 2. To identify the mechanisms that define the dynamic behavior of proteins at the tight junction, and 3. To define the mechanisms and significance of actomyosin-dependent tight junction maintenance and regulation. These studies will be performed using in vitro and in vivo models that include imaging of fluorescent fusion proteins expressed in living cells and tissues and in vivo analysis of immune activation secondary to transgenic manipulation of tight junction permeability. As a result we will significantly advance our understanding of the mechanisms by which membrane, protein, and cytoskeletal dynamics contribute to regulation of transport and barrier function. In addition to providing new fundamental knowledge this is expected to have significant positive effects on human health because it will allow the rational development of new therapeutic strategies for diseases with deficient transport or barrier function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK061931-10S1
Application #
8113501
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Grey, Michael J
Project Start
2001-09-29
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$95,810
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Krug, S M; Bojarski, C; Fromm, A et al. (2018) Tricellulin is regulated via interleukin-13-receptor ?2, affects macromolecule uptake, and is decreased in ulcerative colitis. Mucosal Immunol 11:345-356
Odenwald, Matthew A; Choi, Wangsun; Kuo, Wei-Ting et al. (2018) The scaffolding protein ZO-1 coordinates actomyosin and epithelial apical specializations in vitro and in vivo. J Biol Chem 293:17317-17335
Buckley, Aaron; Turner, Jerrold R (2018) Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease. Cold Spring Harb Perspect Biol 10:
Syed, Sana; Yeruva, Sunil; Herrmann, Jeremy et al. (2018) Environmental Enteropathy in Undernourished Pakistani Children: Clinical and Histomorphometric Analyses. Am J Trop Med Hyg 98:1577-1584
Sallis, Benjamin F; Erkert, Lena; Mo├▒ino-Romero, Sherezade et al. (2018) An algorithm for the classification of mRNA patterns in eosinophilic esophagitis: Integration of machine learning. J Allergy Clin Immunol 141:1354-1364.e9
Almansour, Khaled; Taverner, Alistair; Turner, Jerrold R et al. (2018) An intestinal paracellular pathway biased toward positively-charged macromolecules. J Control Release 288:111-125
Hu, Madeleine D; Ethridge, Alexander D; Lipstein, Rebecca et al. (2018) Epithelial IL-15 Is a Critical Regulator of ?? Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. J Immunol 201:747-756
Hou, Qihang; Ye, Lulu; Liu, Haofei et al. (2018) Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death Differ 25:1657-1670
Edelblum, Karen L; Sharon, Gil; Singh, Gurminder et al. (2017) The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability. Cell Mol Gastroenterol Hepatol 4:285-297
Choi, Wangsun; Yeruva, Sunil; Turner, Jerrold R (2017) Contributions of intestinal epithelial barriers to health and disease. Exp Cell Res 358:71-77

Showing the most recent 10 out of 125 publications