Functional role of fibroblast-like cells in GI muscles


Principal Investigator: Kenton M Sanders
Abstract: DESCRIPTION (provided by applicant): The neuromuscular apparatus in gastrointestinal (GI) muscles is more complicated than previously understood. Enteric motor nerve terminals make very close contacts with 3 types of cells: smooth muscle cells (SMC), interstitial cells of Cajal (ICC) and flibroblast-like cells (FLC). Both ICC and FLC are electrically coupled to SMC. Thus, signals transduced by ICC and FLC can be conveyed electrically throughout the syncytium of SMC. Considerable study has been directed toward SMC and ICC in the past, but there are few studies that have investigated the function of FLC in GI organs. This project will evaluate the function of FLC in mouse and human GI muscles. FLC are specifically labeled with antibodies for PDGFR-alpha. We have developed and verified a transgenic mouse model with constitutive expression of eGFP in PDGFR-alpha+ cells. We will isolate the PDGFR-alpha+ cells and use patch clamp techniques to study the endogenous conductances expressed by these cells and characterize the effects of enteric neurotransmitters on membrane conductances. Preliminary studies demonstrate a large outward current activated by purine neurotransmitters, and the characteristics and pharmacology of this current will be investigated. SMC and ICC respond to purine transmitters with activation of net inward current. Thus, our data suggest that PDGFR-alpha cells mediate purinergic neural responses in GI muscles. We will investigate the innervation of PDGFR + cells using the fluorescence of Ca2+ dyes. We will also use fluorescence activated cell sorting to purify PDGFR-alpha+ cells and characterize the transcriptome of PDGFR + cells. The effects of losing PDGFR + cells on purinergic responses will also be investigated. These studies will improve our understanding of neural regulation of colonic motility and will possibly provide new targets for therapies for motility and functional GI disorders.
Funding Period: 2013-07-01 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Distribution and Ca(2+) signalling of fibroblast-like (PDGFR(+)) cells in the murine gastric fundus
    Salah A Baker
    K M Sanders Department of Physiology and Cell Biology, University of Nevada School of Medicine, MS 352, Reno, NV 89557, USA
    J Physiol 591:6193-208. 2013

Detail Information


  1. pmc Distribution and Ca(2+) signalling of fibroblast-like (PDGFR(+)) cells in the murine gastric fundus
    Salah A Baker
    K M Sanders Department of Physiology and Cell Biology, University of Nevada School of Medicine, MS 352, Reno, NV 89557, USA
    J Physiol 591:6193-208. 2013
    ..Activation of Ca(2+) release is likely to be the signalling mechanism in PDGFRα(+) cells responsible for the transduction of purinergic enteric inhibitory input in gastric fundus muscles...

Research Grants30

  1. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  2. IBD and Mucosal Inflammation, Immunology, and Microbiology of the GI Tract
    Eugene B Chang; Fiscal Year: 2013
    ..Through its cost-effective, enabling technologies and services, the DDRCC has been a major factor in the advancement of scholarship and discovery in IBD and digestive diseases at the University of Chicago. ..
  3. Molecular motors in cell biology
    Yale E Goldman; Fiscal Year: 2013
    ..We anticipate that the proposed work will take us significantly further toward our goal of understanding motility in the normal and pathological function of cells. ..
  4. Roles of DNA methylation in gastrointestinal smooth muscle cells
    Seungil Ro; Fiscal Year: 2013
  5. Generating Human Intestinal Organoids with an ENS.
    James M Wells; Fiscal Year: 2013
    ..Development of an in vitro intestinal organ system containing an ENS would be an ideal platform for high throughput studies aimed at identifying new therapies to improve ENS function in patients with GI motility disorders. ! ..
  6. Interstitial Cells of Cajal in Diabetic Gastropathy
    TAMAS ORDOG; Fiscal Year: 2013
    ..The proposed studies will determine the mechanistic basis for, and set the stage for clinical trials of, novel pharmacological interventions for loss of ICC in motility diseases. ..
    John R Grider; Fiscal Year: 2013
    ..The results would open a new field of study and point the way to new avenues of investigation for pharmacological agents to treat diarrhea and/or constipation. ..
    Charles O Elson; Fiscal Year: 2013
    ..The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients...
  9. Regulation of gastrointestinal neuromuscular function by NIBP/NFkB signaling
    Wenhui Hu; Fiscal Year: 2013
    ..Our studies will highlight the importance of ENS NFkB signaling and provide a novel mechanism for the pathogenesis of neurogastrointestinal disorders. ..
  10. Effect of aging on enteric neural stem cells is dependent on the PI3K/Akt pathway
    Laren Becker; Fiscal Year: 2013
    ..abstract_text> ..
  11. Placode lineage contribution to Hirschsprung's disease
    Takako Makita; Fiscal Year: 2013
  12. Enteric nervous system deficits in Hirschsprung ganglionic bowel
    MELISSA MUSSER; Fiscal Year: 2013
  13. Responsiveness to nicotine of nucleus tractus solitarius neurons
    VICTOR V UTESHEV-GAARD; Fiscal Year: 2013
    ..The experiments here will point to new ways of using nicotinic mechanisms to modify functions of the gastrointestinal system associated with feeding. ..
    Gianrico Farrugia; Fiscal Year: 2013
    ..Our work also has broad implications beyond the GI tract. As Ano-1 is expressed in many organs and tumors including gastrointestinal stromal tumors, our findings will likely apply to several other organs outside of the GI tract. ..
  15. Electrical control of gastric motility
    Kenton M Sanders; Fiscal Year: 2013
    ..e. functional coupling) between the corpus and antrum.. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling...
  16. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  17. Purinergic neurotransmission in the gut
    James J Galligan; Fiscal Year: 2013
    ..This information would help to develop new drug treatments for common motility disorders. ..
  18. Nitrergic Neuro-smooth Muscle Transmission in the Gut
    Raj K Goyal; Fiscal Year: 2013
    ..This proposal is to understand how these disorders are caused and how better treatments for these disorders can be developed. ..
  19. Interactive Signaling Modules in Vascular Inflammation
    Linda H Shapiro; Fiscal Year: 2013
    ..abstract_text> ..
  20. Patterning and Formation of the Neuromuscular Junction
    Weichun Lin; Fiscal Year: 2013
    ..By identifying these regulatory signals, we may be able to provide additional targets for the development of therapeutic strategies to cure, control, or prevent neurodevelopmental disorders and neurodegenerative diseases. ..
  21. Pulmonary Surface Liquid Homeostasis
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  22. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  23. Ednrb Regulation of Gastrointestinal Motility
    KENT CHARLES WILLIAMS; Fiscal Year: 2013
    ..abstract_text> ..
    Michael D Gershon; Fiscal Year: 2013
  25. Severe Enteric Disease: Pathogenesis and Response
    James B Kaper; Fiscal Year: 2013