MicroRNAs are small non-coding RNA molecules that have been implicated in the pathogenesis of different human inflammatory diseases. Recent evidence indicates that manipulation of microRNA expression could have therapeutic potential in inflammatory diseases of different etiologies. We and others have identified that microRNAs are deregulated in Inflammatory Bowel Disease (IBD); however their role and functional importance in IBD pathophysiology is not well understood. Our preliminary evidence revealed that miR-24 expression is specifically up-regulated in colonic biopsies from 2 cohorts of ulcerative colitis (UC), but not Crohn's disease (CD) patients or patients with other GI diseases (irritable bowel syndrome, colorectal cancer). Furthermore, miR-24 expression is higher in colonic biopsies from UC patients with active disease relative to UC patients in remission. Although several microRNAs have been found to be deregulated in different gastrointestinal (GI) diseases, our results demonstrate that miR-24 is specifically deregulated in UC, suggesting an important role in UC pathogenesis. A key question in the microRNA field is the identification of their direct gene targets. Here, we have followed an unbiased integrative computational and molecular analysis and found that miR-24 is potentially involved in UC pathogenesis by regulating a gene network consisting of an inflammatory (HFN4A-PPAR?-NF-?B) circuit by targeting directly HNFA, and an intestinal permeability control mechanism, by modulating directly claudin-7, which affects the ERK and MMP signaling pathways. Thus, these data suggest that miR-24 regulates inflammation and epithelial permeability, both key aspects of UC pathogenesis. On the other hand, suppression of HNF4A and/or claudin-7 reinforced miR-24 increased expression, suggesting the presence of a feedback loop network. This is the first evidence describing a microRNA to act as a rheostat of the inflammatory response and intestinal permeability, through regulation of a feedback loop network. Here, we will examine the novel hypothesis that the miR-24 network plays an important role in UC pathophysiology by regulating inflammatory and intestinal permeability mechanisms. Based on strong preliminary findings the following aims will address this overall hypothesis.
Aim 1 will evaluate the role of miR-24 ? HNF4A network on controlling the inflammatory responses in UC.
Aim 2 will characterize the molecular mechanism of miR-24 on intestinal epithelial permeability. Use of human UC patient tissues will confirm the UC relevance of the findings in aims 1 and 2.
Aim 3 will examine the therapeutic potential of miR- 24 inhibition, by administering a novel chemically-stable miR-24 inhibitor (UCDI-1), in mouse models of experimental colitis (in vivo) and in freshly isolated colonic explants from UC patients (ex vivo). Understanding the miR-24 molecular network will not only provide novel insights on the role of miR-24 in UC pathophysiology, but it may also determine the therapeutic potential of miR-24 inhibition by UCDI-1 in UC.

Public Health Relevance

Ulcerative colitis (UC) is one of the major illnesses in the gastrointestinal tract associated with several fatal complications and accelerated incidence in the United States over the last several decades. Findings from the proposed studies should advance our understanding on the molecular mechanism(s) underlying UC and define the mechanism of action of non-coding RNAs in the pathophysiology of intestinal inflammation. Results from our studies potentially will form the basis to evaluate the miR-24 chemical inhibitor (UCDI-1) to suppress intestinal inflammation in ulcerative colitis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110003-04
Application #
9753213
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Soroosh, Artin; Koutsioumpa, Marina; Pothoulakis, Charalabos et al. (2018) Functional role and therapeutic targeting of microRNAs in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 314:G256-G262
Fang, Kai; Law, Ivy Ka Man; Padua, David et al. (2018) MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis. Am J Pathol 188:586-599