This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Smooth muscle (SM) hypertrophy occurs in a variety of visceral muscles in response to pathophysiological conditions. We have developed a small intestine partial obstruction (PO) model in which the SM hypertrophy is oral but not aboral to the site of PO, to study the remodeling that occurs in smooth muscle cells (SMCs) during hypertrophy and/or hyperplasia. microRNAs (miRNAs) regulate vital cellular functions in SMCs such as differentiation, proliferation, and apoptosis. Our preliminary microarray analysis reveals that gene expression in the PO model is dramatically different from that of control muscles. We have also identified a unique set of miRNAs that are highly expressed in the small intestine of mice and humans with miR-143 and miR-145 being particularly abundant. These miRNAs are also abundantly expressed in sorted SMCs and both are down-regulated in the PO model. This has led to the hypothesis that SM hypertrophy is regulated, in part, by SMC-dependent miRNAs. To determine the role of miRNAs in the development of small intestine hypertrophy, the following three aims will be addressed:
Aim 1 : Identify the miRNAs expressed in small intestine SMCs and the changes which occur with the development of SMC hypertrophy;
Aim 2 : Identify the messenger RNAs (mRNAs) expressed in small intestine SMCs and the changes which occur with the development of hypertrophy;
Aim 3 : Identify the miRNAs specifically regulating the genes associated with hypertrophy. Several molecular, genetic, and bioinformatic approaches will be used to develop a functional link between miRNA and target gene expression in the hypertrophic SMCs.
For Aim 1, SMC hypertrophy will be studied in our PO model generated in the SM-specific Cre/eGFP mice which permit highly specific SMC sorting and 454 sequencing (pyrosequencing) techniques.
For Aim 2, we will identify hypertrophy-dependent genes using GeneChip analyses of the mRNAs isolated from sorted SMCs.
For Aim 3, we will identify the miRNAs regulating hypertrophy genes by first relating miRNAs to target genes using bioinformatics and then validating these relationships using cutting edge molecular biology techniques. We will primarily focus on miR-143 and miR-145 and their target genes to see how they regulate the development of SMCs during hyperplasia and/or hypertrophy. Understanding changes in gene expression in SMCs provides an exciting new opportunity for understanding the regulation of phenotype in SM pathophysiological conditions. Identifying the genetic markers associated with hypertrophy will aid in the development of miRNA drugs that have the potential to normalize mRNA targets that are responsible for hypertrophy and thus reverse some of the unwanted pathological changes that occur in these disorders.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018751-08
Application #
8360519
Study Section
Special Emphasis Panel (ZRR1-RI-B (01))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$208,637
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Brijs, Jeroen; Hennig, Grant W; Gräns, Albin et al. (2017) Exposure to seawater increases intestinal motility in euryhaline rainbow trout (Oncorhynchus mykiss). J Exp Biol 220:2397-2408
Heredia, Dante J; Schubert, Douglas; Maligireddy, Siddhardha et al. (2016) A Novel Striated Muscle-Specific Myosin-Blocking Drug for the Study of Neuromuscular Physiology. Front Cell Neurosci 10:276
Schuster, Andrew; Skinner, Michael K; Yan, Wei (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environ Epigenet 2:
Scurry, Alexandra N; Heredia, Dante J; Feng, Cheng-Yuan et al. (2016) Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy. J Neuropathol Exp Neurol 75:334-46
Bao, Jianqiang; Tang, Chong; Yuan, Shuiqiao et al. (2015) UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome. Development 142:352-62
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
Winbush, Ari; Gruner, Matthew; Hennig, Grant W et al. (2015) Long-term imaging of circadian locomotor rhythms of a freely crawling C. elegans population. J Neurosci Methods 249:66-74
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
Yuan, Shuiqiao; Stratton, Clifford J; Bao, Jianqiang et al. (2015) Spata6 is required for normal assembly of the sperm connecting piece and tight head-tail conjunction. Proc Natl Acad Sci U S A 112:E430-9
Ortogero, Nicole; Hennig, Grant W; Luong, Dickson et al. (2015) Computer-assisted annotation of small RNA transcriptomes. Methods Mol Biol 1218:353-64

Showing the most recent 10 out of 92 publications