Gastrointestinal (Gl) neuromuscular disorders are characterized by motility dysfunctions. Gl motility is mainly regulated by three types of neuro-effector cells, Smooth muscle cells (SMCs), Interstitial cells of Cajal (ICC), and PDGFRa+ cells, all of which are electrically coupled to form the integrated network referred as SIP syncytium. To understand Gl motility, SIP cells should be studied together because each of these cells modifies the behaviors ofthe other cells. This Program seeks to uncover a variety of elements in SIP cells that affect Gl motility in beneficial or pathological ways: 1) molecular mechanisms of pacemaker activity and regulation of responses to neurotransmission;2) purine signaling and metabolism pathways;and 3) phenotypic and genetic changes of ICC after loss and restoration of c-KIT expression. Each of these projects will interact with the informatics and data management capabilities provided by the Core. The Core employs next-generation sequencing (mRNA-seq) that provides gene expression profiles of each SIP cell type on a genome-wide scale with very high resolution. The genome-wide transcripts will provide all genes, isoforms, and splice variants that are expressed in each cell type. In addition, they will also identify changes in expression levels for individual genes, isoforms, and splice variants with superior resolution in pathologically changed SIP cells. This powerful genome-wide approach to study gene expression will reveal: 1) patterns of changes in the entire transcriptome of SIP cells;2) identify cell-specific genes, isoforms, and splice variants; 3) examine individual transcripts for functional studies;4) link transcriptional information to potential physiologic functions ofthe cells;and 5) identify genes that control phenotypic changes ofthe cells.

Public Health Relevance

The discovery of important elements that are anticipated with the transcriptome study ofthe SIP cells will provide a road map to study in detail the functions of each cell type and aid in the development of hypotheses that will progress to human studies, which will stimulate the development of clinical therapeutics to treat human subjects with motility disorders where these cell types may be pathologically involved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK041315-26
Application #
8742143
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J3))
Project Start
Project End
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
26
Fiscal Year
2014
Total Cost
$163,444
Indirect Cost
$49,546
Name
University of Nevada Reno
Department
Type
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Sanders, Kenton M; Salter, Anna K; Hennig, Grant W et al. (2014) Responses to enteric motor neurons in the gastric fundus of mice with reduced intramuscular interstitial cells of cajal. J Neurogastroenterol Motil 20:171-84
Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don et al. (2014) Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Physiol Cell Physiol 306:C705-13
McCann, Conor J; Hwang, Sung-Jin; Hennig, Grant W et al. (2014) Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal. J Neurogastroenterol Motil 20:326-37
Durnin, Leonie; Hwang, Sung Jin; Kurahashi, Masaaki et al. (2014) Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut. Proc Natl Acad Sci U S A 111:15821-6
Okamoto, T; Barton, M J; Hennig, G W et al. (2014) Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil 26:556-70
Drumm, Bernard T; Koh, Sang Don; Andersson, Karl-Erik et al. (2014) Calcium signalling in Cajal-like interstitial cells of the lower urinary tract. Nat Rev Urol 11:555-64
Mutafova-Yambolieva, Violeta N; Durnin, Leonie (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144:162-91
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Kurahashi, Masaaki; Nakano, Yasuko; Peri, Lauren E et al. (2013) A novel population of subepithelial platelet-derived growth factor receptor *-positive cells in the mouse and human colon. Am J Physiol Gastrointest Liver Physiol 304:G823-34
Keef, K D; Saxton, S N; McDowall, R A et al. (2013) Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter. J Physiol 591:1489-506

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