The enteric nervous system (ENS) plays an important role in the regulation of gastrointestinal (GI) functions. Morphological changes and functional abnormalities in adult ENS have been associated with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), gastroparesis and chronic constipation/diarrhea. The immune and inflammatory responses, in addition to genetic and environmental factors, play critical roles in the pathogenesis of these GI diseases. Most of the immune responses are mediated by the signaling of nuclear factor kB (NFkB). During the current funding period, we demonstrated that NFkB signaling in smooth muscle mediates inflammation-induced inhibition of colonic smooth muscle contraction. There is a fundamental gap in understanding how NFkB signaling from the ENS influences GI diseases. The long-term goal is to understand the role of NFkB signaling in the regulation of GI functions in health and during inflammation. The objective of this renewal is to elucidate the importance of enteric neuron- and astroglia-specific NFkB signaling in regulating GI neuromuscular function. The central hypothesis is that enteric neuronal NFkB signaling is required for the maintenance of GI functional integrity while enteric glial NFkB signaling regulates neuronal functions under normal conditions but mediates inflammatory responses under inflamed conditions. This hypothesis will be tested by parallel studies on the effects of enteric neuronal and astroglial NFkB signaling manipulation on GI contractility under normal and inflamed conditions using 4 lines of conditional gene knockout or knockin mice.
In aim 1, we will use enteric neuron-specific conditional knockout of NIBP or knockin of IKK2CA (Constitutively Active form) mice to inactivate or overactivate enteric neuronal NFkB signaling, respectively.
In aim 2, we will use GFAP-dnIkB? or GFAP-IKK2CA transgenic mice to inactivate or overactivate enteric astroglial NFkB signaling, respectively. In both aims, we will determine changes in (a) chemical coding and morphology of enteric neurons and glial cells, (b) nerve-stimulated and agonist-induced GI contraction/relaxation, and (c) expression patterns of contractile proteins and inflammatory mediators in smooth muscles. Completion of these studies will demonstrate for the first time the importance of neuronal NFkB signaling in the maintenance of ENS functional integrity and astroglial NFkB signaling in facilitating gliotic and inflammatory responses that contribute to the development and progression of chronic inflammation. This proposal is innovative both in concept implicating neuronal NIBP in the regulation of ENS functions and astroglial NFkB in the regulation of inflammation, and in the use of novel neuron- and astroglia-specific transgenic mice. Our studies will highlight the importance of ENS NFkB signaling and provide a novel mechanism for the pathogenesis of neurogastrointestinal disorders.

Public Health Relevance

The proposed research is relevant to public health because the discovery of a novel function of NIBP/NFkB signaling in enteric neurons and glial cells is ultimately expected to increase the understanding of the pathogenesis of gastrointestinal diseases. It also shed light on the therapeutics for gastrointestinal inflammation and functional disorders. The project is relevant to NIH mission because the fundamental knowledge of enteric nervous system and inflammatory regulation help to extend healthy life and reduce burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075964-07
Application #
8550804
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Hamilton, Frank A
Project Start
2006-07-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$320,576
Indirect Cost
$102,874
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Zhang, Y; Bitner, D; Pontes Filho, A A et al. (2014) Expression and function of NIK- and IKK2-binding protein (NIBP) in mouse enteric nervous system. Neurogastroenterol Motil 26:77-97
Pontes, Adalto; Zhang, Yonggang; Hu, Wenhui (2013) Novel functions of GABA signaling in adult neurogenesis. Front Biol (Beijing) 8:
Zhang, Yonggang; Li, Fang; Liu, Shu et al. (2012) MEKK1-MKK4-JNK-AP1 pathway negatively regulates Rgs4 expression in colonic smooth muscle cells. PLoS One 7:e35646
Li, Fang; Murthy, Karnam S; Khalili, Kamel et al. (2010) Cloning and characterization of rabbit Rgs4 promoter in gut smooth muscle. Gene 451:45-53
Li, Fang; Hu, Danielle Y; Liu, Shu et al. (2010) RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells. Am J Physiol Cell Physiol 299:C1418-29
Hu, Wenhui; Li, Fang; Mahavadi, Sunila et al. (2009) Upregulation of RGS4 expression by IL-1beta in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3beta pathway. Am J Physiol Cell Physiol 296:C1310-20
Hu, Wenhui; Li, Fang; Mahavadi, Sunila et al. (2008) Interleukin-1beta up-regulates RGS4 through the canonical IKK2/IkappaBalpha/NF-kappaB pathway in rabbit colonic smooth muscle. Biochem J 412:35-43
Hu, Wenhui; Mahavadi, Sunila; Li, Fang et al. (2007) Upregulation of RGS4 and downregulation of CPI-17 mediate inhibition of colonic muscle contraction by interleukin-1beta. Am J Physiol Cell Physiol 293:C1991-2000