Gastrointestinal (GI) neuromuscular disorders (motility disorders) are characterized by dysfunctions of three types of key cells: interstitial cels of Cajal (ICC), enteric nervous system (ENS), and smooth muscle cells (SMCs), which cooperatively control SM motility in the GI tract. ENS and ICC generate complex rhythmic motor behavior and spontaneous electrical slow waves, respectively, both of which control SMCs, the final effectors for muscle contraction and muscle relaxation. Although there has been a significant amount of work investigating the effects of ENS and ICC dysfunction in GI motility disorders, the dysfunction of SMCs has received much less attention. The gap in the knowledge of SMC dysfunction needs to be addressed, since the three types of cells are physically associated and functionally working together: dysfunction of one cell type can affect the other two. This present project seeks to uncover a molecular mechanism for understanding how SMCs are remodeled during the development of GI motility disorders. We have recently reported that GI SMCs require microRNAs (miRNAs) for the development and survival of animals, and that the phenotypes of GI SMCs are controlled by serum response factor (SRF)-dependent microRNAs. In addition, our preliminary study suggested that the phenotypic change (hypertrophy) of SMCs is linked to dysregulation of a unique set of SRF-dependent miRNAs which are regulated by epigenetic DNA methylation. To study this new molecular mechanism, we generated six transgenic animal models that display abnormal phenotypes of SMCs during the embryonic and post-natal development of the cells. In this project, we propose three specific aims: define the roles of SRF-dependent miRNAs during the development of GI SMCs, define the roles of DNA methylation during the development of GI SMCs, and discover the roles of DNA methyltransfertase (Dnmt1)-targeting miRNAs that regulate GI SMC hypertrophy. Completion of the specific aims of this project will provide an exciting new mechanism for understanding how the SRF-dependent miRNA genes are epigenetically reprogrammed in the SMCs of GI neuromuscular disorders. Identifying the epigenetic changes will aid not only in the development of a diagnostic tool for hypertrophy-related diseases, but also of a therapeutic target that has the potential to reverse the epigenetic changes that are responsible for these pathological conditions, and thus possibly reverse some of the unwanted pathological changes that occur in these disorders.

Public Health Relevance

Dysfunction of smooth muscle cells (SMCs) is linked to gastrointestinal (GI) neuromuscular disorders, but the molecular mechanism of GI SMC dysfunction is unknown. This study seeks to uncover how SMCs are genetically remodeled during the development of GI neuromuscular disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094886-01
Application #
8277144
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Carrington, Jill L
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$317,900
Indirect Cost
$91,085
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Jorgensen, Brian G; Berent, Robyn M; Ha, Se Eun et al. (2018) DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease. Cell Death Dis 9:474
Ha, Se Eun; Lee, Moon Young; Kurahashi, Masaaki et al. (2017) Transcriptome analysis of PDGFR?+ cells identifies T-type Ca2+ channel CACNA1G as a new pathological marker for PDGFR?+ cell hyperplasia. PLoS One 12:e0182265
Lee, Moon Young; Ha, Se Eun; Park, Chanjae et al. (2017) Transcriptome of interstitial cells of Cajal reveals unique and selective gene signatures. PLoS One 12:e0176031
Lee, Moon Young; Park, Chanjae; Ha, Se Eun et al. (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12:e0171262
Ro, Seungil (2016) Multi-phenotypic Role of Serum Response Factor in the Gastrointestinal System. J Neurogastroenterol Motil 22:193-200
Park, C; Lee, M Y; Slivano, O J et al. (2015) Loss of serum response factor induces microRNA-mediated apoptosis in intestinal smooth muscle cells. Cell Death Dis 6:e2011
Lee, Moon Young; Park, Chanjae; Berent, Robyn M et al. (2015) Smooth Muscle Cell Genome Browser: Enabling the Identification of Novel Serum Response Factor Target Genes. PLoS One 10:e0133751