Acute and chronic diarrheal diseases are major contributors to mortality and morbidity in developing countries where they are the second most frequent cause of infant mortality and to morbidity in the USA where they represent a huge economic burden. Lacking approved, safe and highly effective anti-diarrheal drugs, a NIH Single Topic Conference held 9/2011 concluded that development of drug therapy to treat all forms of diarrhea has a high research priority with the goal of reducing the duration and amount of diarrhea. The needed information that was lacking for diarrheal drug development was not felt to be in our understanding of the pathophysiology of diarrhea as due to inhibition of Na+ absorption with or without stimulation of Cl- secretion. Rather it was lack of information about the distribution and extent of expression of major ion transport proteins in the normal human intestine, how this changes with age, and how transporter activity and expression changes with various diarrheas. This R24 represents a collaborative effort of 5 principle investigators from three institutions all of whom have a primary research interest in intestinal epithelial transport and its regulation, but who bring expertise in several different but complementary areas of research which are needed to address the aims of this project. In this way we propose to provide the scientific underpinning needed for current and future development of anti-diarrheal drugs.
The Aims of this project are to I. Develop a catalogue of the intestinal expression of potential anti-diarrheal drug targets in healthy controls and diarrheas using archived human intestine, mouse intestine and human enteroids; standardize model diarrheas in mouse small intestine and human enteroids; and perform a phenotypic screen using human enteroids to identify unique drugs to treat the diarrhea models. II. Determine changes in function of specific Na+ absorptive and Cl- secretory transporters in the diarrhea models and the mechanisms by which they occur, including effects of the newly identified anti-diarrheal drugs. III. Determine the efficacy of novel anti-secretory and pro-absorptive therapeutics in in vivo and ex vivo diarrheal models. High throughput screen for NHE3 stimulators.

Public Health Relevance

This project will provide the background to develop effective drug therapy for diarrhea by a collaboration of 5 PIs (3 institutions) with complementary areas of expertise. The aims are to I. Catalog the expression pattern of potential drug targets in human and mouse intestine normally and in model diarrheas. II. Measure changes in transporter activity in model diarrheas. III. Determine efficacy of novel drugs in these models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
3R24DK099803-05S1
Application #
9892562
Study Section
Program Officer
Shea-Donohue, Terez
Project Start
2019-04-01
Project End
2020-06-30
Budget Start
2019-05-23
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Singh, Varsha; Yang, Jianbo; Yin, Jianyi et al. (2018) Cholera toxin inhibits SNX27-retromer-mediated delivery of cargo proteins to the plasma membrane. J Cell Sci 131:
Zou, Winnie Y; Blutt, Sarah E; Zeng, Xi-Lei et al. (2018) Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation. Cell Rep 22:1003-1015
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; MoƱino-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
Yin, Jianyi; Tse, Chung-Ming; Avula, Leela Rani et al. (2018) Molecular Basis and Differentiation-Associated Alterations of Anion Secretion in Human Duodenal Enteroid Monolayers. Cell Mol Gastroenterol Hepatol 5:591-609
Lee, Sujin; Cil, Onur; Diez-Cecilia, Elena et al. (2018) Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1. J Med Chem 61:3209-3217
Yu, Huimin; Hasan, Nesrin M; In, Julie G et al. (2017) The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology. Annu Rev Physiol 79:291-312
Saxena, Kapil; Simon, Lukas M; Zeng, Xi-Lei et al. (2017) A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection. Proc Natl Acad Sci U S A 114:E570-E579
Son, Jung-Ho; Zhu, Jie S; Phuan, Puay-Wah et al. (2017) High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators. J Med Chem 60:2401-2410
Thiagarajah, Jay R; Chang, Jeffrey; Goettel, Jeremy A et al. (2017) Aquaporin-3 mediates hydrogen peroxide-dependent responses to environmental stress in colonic epithelia. Proc Natl Acad Sci U S A 114:568-573

Showing the most recent 10 out of 50 publications