Caroline Cobine, Ph.D.

Summary

I first came to the University of Nevada, Reno School of Medicine as an undergraduate student from Queen's University Belfast participating in the International Undergraduate Research Program.   During that year I worked with Dr. Kathleen Keef and developed an interest in smooth muscle physiology.  After completion of my Bachelors of Science degree at Queen's I returned to Reno and ultimately received my Ph.D. from the Cellular and Molecular Pharmacology and Physiology (CMPP) Graduate Program at UNR under the supervision of Dr. Keef.  

My research is focused on the mechanisms underlying the contractile activities of visceral smooth muscles (particularly gastrointestinal).  Much of my work has been centered on the role of interstitial cells (interstitial cells of Cajal, ICC; PDGFRα ⁺ cells) in the internal anal sphincter (IAS).  The IAS is responsible for >70% of resting anal pressure and therefore plays a pivotal role in the maintenance of fecal continence.  Despite the importance of this muscle, it is the least studied region of the gastrointestinal tract (only 0.5% of published papers).

Of particular interest is the role of ICC and PDGFRα ⁺ cells in tone generation and in mediating neural responses.  To this end many of our studies utilize transgenic mouse models expressing GFP and the genetically encoded Ca ²⁺ indicator GCaMP in specific cell populations (i.e., smooth muscle cells, ICC, PDGFRα ⁺ cells).  Methodologies used include: calcium imaging with spinning disc confocal microscopy, immunohistochemistry, histology, isometric tension recording, patch clamp recording, microelectrode recording, fluorescence-activated cell sorting, PCR, western blot. Most recently our studies have revealed that two distinct populations of intramuscular ICC are present within the IAS.  One exhibits calcium transients that occur at a similar frequency to electrical slow waves suggesting that these cells are responsible for pacemaker activity.   A second population of ICC appear to mediate neural responses.  The mechanisms underlying these responses are a subject of further research.  My teaching responsibilities include teaching Abdominal, Pelvic and Musculoskeletal Anatomy and Endocrine Physiology to first year medical and physician's assistant program students and Endocrine Physiology to graduate students within the Molecular Biosciences (CMPP) program.

Selected Publications

Published Papers:

1. Keef, KD and Cobine, CA.  Control of motility in the internal anal sphincter.  J Neurogastroenterol Motil. 2019 Apr 30;25(2):189-204.  Review
2. Cobine, CA, McKechnie, M, Brookfield, RJ, Hannigan, KI and Keef, KD.  Comparison of inhibitory neuromuscular transmission in the Cynomolgus monkey IAS and rectum: special emphasis on differences in purinergic transmission.  J Physiol. 2018 Nov 15;596(22):5319-5341. 
3. Rembetski, BE, Cobine, CA and Drumm, BT.  Laboratory practical to study the differential innervation pathways of urinary tract smooth muscle.  Adv Physiol Educ. 2018 Jun 1;42(2):295-304.
4. Baker, SA, Drumm, BT, Cobine, CA, Keef, KD and Sanders, KM.  Inhibitory Neural Regulation of the Ca ²⁺ Transients in Intramuscular Interstitial Cells of Cajal in the Small Intestine.  Front Physiol. 2018 Apr 9;9:328.
5. Drumm, BT, Rembetski, BE, Cobine, CA, Baker, SA, Sergeant, GP, Hollywood, MA, Thornbury, KD and Sanders, KM.  Ca2+ signalling in mouse urethral smooth muscle in situ: Role of Ca2+ stores and Ca2+ influx mechanisms. J Physiol. 2018 Apr 15;596(8):1433-1466
6. Cobine, CA, Hannah, EE, Zhu, MH, Lyle, HE, Rock, JR, Sanders, KM, Ward, SM, and Keef, KD.  ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter.  J Physiol. 2017 Mar 15;595(6):2021-2041.  Editor's Choice.
7. Cobine, CA, Sotherton, AG, Peri, LE, Sanders, KM, Ward, SM and Keef, KD.  (2014)  Nitrergic neuromuscular transmission in the mouse internal anal sphincter is accomplished by multiple pathways and post-junctional effector cells.  Am J Physiol Gastrointest Liver Physiol 2014 Dec 1;307(11):G1057-72.
8. Keef, KD, Saxton, SN, McDowall, RA, Kaminski, RE, Duffy, AM, Cobine, CA.  (2013) Functional role of vasoactive intestinal peptide in inhibitory motor innervation in the mouse internal anal sphincter.  J Physiol. 2013 Mar 15;591(Pt 6):1489-506.
9. Cobine, CA, Hennig, GW, Kurahashi, M, Sanders, KM, Ward, SM, Keef, KD. (2011) Relationship between interstitial cells of Cajal, fibroblast-like cells and inhibitory motor nerves in the internal anal sphincter. Cell Tissue Res 2011 Apr;344(1):17-30
10. Cobine, CA, Hennig, GW, Bayguinov, YR, Hatton, WJ, Ward, SM, Keef, KD.  (2010) Interstitial Cells of Cajal in the Cynomolgus monkey rectoanal region and their relationship to sympathetic and nitrergic nerves.  Am J Physiol Gastrointest Liver Physiol 298:G643-656, 2010.
11. Cobine, CA, Fong, M, Hamilton, R, Keef, KD.  (2007) Species dependent differences in the actions of sympathetic nerves and noradrenaline in the internal anal sphincter.  Neurogastroenterol Motil. 2007 Nov;19(11):937-5.
12. Keef, K, Cobine, C. (2008) Author reply to "Sympathetic (adrenergic) innervation modulates but does not generate basal tone in the internal anal sphincter smooth muscle".  Gastroenterology 2008 Jun;134(7):2181-2.
13. Cobine, CA, Callaghan, BP, Keef, KD.  (2007) Role of L-type calcium channels and PKC in active tone development in rabbit coronary artery.  Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3079-88.
14. Duffy, AM, Cobine, CA, Keef, KD.  (2012) Changes in neuromuscular transmission in the W/W ^v mouse internal anal sphincter.   Neurogastroenterol Motil. 2012 Jan;24(1):e41-55.
15. Hall, KA, Ward, SM, Cobine, CA and Keef, KD.  (2014)  Spatial organization and coordination of slow waves in the mouse anorectum.  J Physiol. 2014 Sep 1;592(Pt 17):3813-29.    

Book Chapter:

1. Keef, K and Cobine, C.  Generation of tone by gastrointestinal sphincters. In Smooth Muscle Spontaneous Activity.  Eds. Hashitani and Lang, Springer 2019. Adv Exp Med Biol. 2019;1124:47-74.