| |
 |
Diabetes Research Group
Laboratory of Molecular Signalling in Diabetes
5358 - 2350 Health Sciences Mall, University of British Columbia
Vancouver, BC Canada V6T 1Z3
MSFHR Scholar, CDA Scholar, JDRF Scholar & CIHR New Investigator
Phone: 604-822-7187
Fax: 604-822-2316
Email: James.d.johnson@ubc.ca
Click here to access Dr. Johnson's page on the Diabetes Research Group website |
|
Training
PhD Cell Biology and Physiology, University of Alberta
Post-Doctoral Fellowship, Washington University Medical Center
Current Position
Associate Professor, Cellular & Physiological Sciences and Surgery, University of British Columbia
Major Awards
2009 Researcher of the Year - Department of Cellular and Physiological Sciences
2008 Runner-up for Department of Cellular and Physiological Sciences Researcher of the Year
2008 UBC Faculty of Medicine Distinguished Achievement Award for Excellence in Basic Science Research
2007 Murray L Barr Award, Canadian Association for Anatomy Neurobiology and Cell Biology
2006 Canadian Diabetes Association Scholarship (declined)
2006 Canadian Institute of Health Research New Principal Investigator Award
2005 Juvenile Diabetes Research Foundation Career Development Award
2003 Canadian Institutes for Health Research Senior Post-Doctoral Fellowship Phase 2
Most Significant Contributions
1. Insulin signaling in primary b-cells. We demonstrated directly that insulin is a potent anti-apoptotic factor in human and mouse islets cells (PNAS, 2006). This paper also contains the first dynamic analysis of the human islet proteome. We have also published that insulin increases insulin synthesis, but does not exert robust effects on its own secretion in human islet cells (Molecular and Cellular Endocrinolgy, 2005). We reported first that human b-cells possess intracellular calcium stores sensitive to NAADP and that this messenger is involved in insulin signaling (PNAS, 2002; Diabetes, 2006; Endocrinology 2010). We also showed for the first time that insulin stimulates primary b-cell proliferation and identified Raf-1 as a critical kinase in b-cell insulin signaling and survival (Endocrinology, 2008 & 2010; JBC, 2007; Cell Cycle, 2008). Together, these studies provided the first direct evidence that physiological concentrations of insulin can acutely regulate b-cell fate and identified novel mechanisms. We have also collaborated to examine growth factor signaling in islets (PNAS, 2006; JBC, 2004; JCI, 2004). Several new manuscripts in this area have been prepared. This work is partially supported by JDRF via two grants.
2. Lipotoxicity in pancreatic b-cells. We have performed proteomic screens to identify novel targets of lipotoxic fatty acids in pancreatic b-cells. A major manuscript arising from this work was published PNAS (2008) and became the source of media attention, and the subject of an invited review for Cell Cycle (2008). We have also published a manuscript on the mobilization of ER calcium by palmitate in the American Journal of Physiology (2009). In collaboration with others, we also determined that mice lacking a b-cell cholesterol transporter have impaired insulin secretion (Nature Medicine, 2007). The Canadian Diabetes Association supports this research program and has renewed this grant for another 3 years.
3. The b-cell RyR2/calpain-10 apoptosis pathway. This was the first demonstration in any cell type that blocking ryanodine receptor (RyR) calcium release channels leads to apoptosis and the first demonstration of a physiological function for calpain-10 (J. Biol. Chem. 2004). The identification of a calpain-10-dependent apoptosis pathway, largely independent of caspase-3, provided new insights into the complexity of b-cell apoptosis mechanisms. Calpain-10 was also required for cell death induced by free fatty acids and hypoglycemia, but not other stresses. Both RyR and calpain-10 represent potential targets for drugs aimed at reducing apoptosis in islet transplantation and diabetes. A related manuscripts detailed the role of RyR in insulin secretion and calcium homeostasis in human islet cells (FASEB J. 2004) and another showed that mice lacking CD38, an enzyme upstream of RyR, have increased b-cell apoptosis (Diabetes, 2006). We also examined the effects of a mitochondrial Ca2+ uptake inhibitor on human and mouse primary b-cells (Eur. J. Pharm, 2007) and the role of presenilin in adult b-cells (Diabetologia, 2007; JBC, 2008). We have also shown that over-activity of RyR and IP3R can contribute to b-cell apoptosis (Diabetes 2008). CIHR supports this work and has renewed the grant for another 3 years.
4. The role of pdx1 in the control of islet apoptosis. This provided the first indication that Pdx-1 deficiency plays a prominent role in b-cell apoptosis, rather than a cell-autonomous role in the day-to-day physiology of beta-cells, as had been suggested by others. Our findings establish a new paradigm for genes associated with maturity onset diabetes of the young (MODY) and have provoked substantial discussion among researchers in the field since they were published in the Journal of Clinical Investigation (2003)(already cited >132 times). We have since found novel pro-survival effects of insulin that are mediated by Pdx-1 (PNAS, 2006). While the majority of this work was performed as a post-doctoral fellow, I have recently published a single-author review on b-cell apoptosis in MODY (Can. J. Diabetes. 2007). We have recently published studies with real-time tracking of Insulin and Pdx1 promoter activity that demonstrate the kinetics of maturation in single beta-cells (Endo. 2008; Diabetologia 2010). This work is funded by the Stem Cell Network.
5. Function-specific and agonist-specific calcium stores in endocrine cells. These studies represent the first comprehensive comparison of the role of two different calcium stores in the control of basal hormone secretion, stimulated hormone secretion, hormone synthesis and gene expression in any endocrine cell type. We also showed, for the first time in any endocrine cell type, that two closely-related neuropeptides generate spatially and temporally distinct calcium signals by mobilizing different sets of intracellular calcium stores. These findings appeared in a series of 8 papers published in the J. Neuroendocrinology (2), American Journal of Physiology (2), Cell Calcium, Cellular and Molecular Endocrinolgy, and General and Comparative Endocrinology between 2001 and 2005. Two additional manuscripts have been prepared. We have continued to examine multiple calcium stores in b-cells with a previous grant and studentships from NSERC. |
The Laboratory of Molecular Signalling in Diabetes is a dynamic team of individuals focused on understanding the causes of type 1 and type 2 diabetes, as well as the complications of these diseases, at a molecular level. Our studies are guided by the discovery of genes, associated gene networks and lifestyle risk factors linked to diabetes risk and by known risk factors that predispose individuals to diabetes. The common forms of both type 1 diabetes and type 2 diabetes appear to result from a combination of genetic and acquired factors, and both diseases are increasing in prevalence. Despite some major advances, we do not yet understand the root causes of diabetes, nor do we fully understand how diabetes increases the risk of other diseases including cancer and heart disease. Our laboratory has projects on diabetes, cancer, heart failure, arrhythmias, obesity, and longevity all using state-of-the-art tools that investigate problems from the cellular level to the whole organism level. We collaborate widely with experts at UBC and abroad.
As a major focus, we study the role of the insulin-secreting pancreatic beta-cell in type 1 diabetes, type 2 diabetes, and other rare forms of diabetes. We are particularly interested in determining the molecular signalling pathways that control the survival and function of these insulin-secreting cells. These signals represent the key to understanding the disease and designing rational treatments.
In order to understand these processes, we employ state-of-the-art techniques including: molecular imaging, molecular biology and in vivo studies. In many cases we examine the role of a particular gene from the single-cell level (where the exact mechanism of its action can be established) to the level of the whole organism (where its role in total body energy homeostasis can be evaluated). We also have an increasingly broad interest the role of insulin in obesity and insulin resistance, focusing on the brain and adipocyte as targets. We are also investigating the molecular links between insulin and cancer, particularly focusing on pancreatic cancer.
In the Laboratory of Molecular Signalling in Diabetes, we believe fundamental science is essential to finding a cure to diabetes and its complications. We also believe that diseases in distinct tissues involve a common set of pathways, and therefore believe that lessons from research on a specific disease can help us answer outstanding questions in seemingly unconnected systems.
The lab is filled with motivated, hard-working staff, students and post-doctoral fellows (each with their own distinct projects) working toward this goal. |
Lipotoxicity, Human Diabetes Genes and Gene-Environment Interactions in Type 2 Diabetes
One of the causes of type 2 diabetes is an increase in pancreatic beta-cell death, leading to insufficient insulin. Unfortunately, we still do not understand which genes are required for beta cell survival in the presence of high fat, so we are unable to design effective treatments to stop beta-cell death. For decades, medical research has primarily used a 'candidate' gene approach to study known proteins, one at a time, for their role in specific disease states. With the emergence of new technology and systems biology, it is now possible to simultaneously examine virtually all genes or proteins in a cell. These unbiased approaches reveal novel findings that could not have been predicted based on prior knowledge. With CDA-support, we have used unbiased proteomic analysis to reveal part of the mechanism by which fatty acids kill beta-cells via ER-stress. The objective of this research program is to continue our proteomics-guided efforts to understand how fatty acids kill beta cells. In particular, we will focus how fatty acids alter the beta-cell's quality control system for proteins such insulin. We use advanced molecular biology and microscopy to determine how fatty acids lead to the degradation of key proteins in beta-cells. This study will improve our understanding of the underlying causes of diabetes as we search for ways to prevent, manage and cure this disease. This project is supported by a grant-in-aid from the Canadian Diabetes Association.
Calcium-Dependent Signal Transduction in Pancreatic Beta-Cells
All cellular processes are controlled by signals. Defects in the transduction of these signals cause disease. Although we have learned a great deal about the events that control a variety of functions in pancreatic beta-cells, the signalling defects that cause diabetes remain to be elucidated. A major interest in the laboratory is the role of intracellular calcium stores, including those sensitive to IP3, ryanodine and NAADP, in beta-cell survival and function. Intracellular calcium homeostasis is vital to the survival of all cell types. We are particularly interested in the mechanisms by which dysfunctional intracellular calcium signalling leads to programmed cell death. Intracellular calcium stores have been linked to diabetes in previous studies. There is also strong evidence that ER-stress, resulting from lowered ER calcium levels in the beta-cell, plays a significant role in both rare and common forms of diabetes. We are currently using advanced biochemical and molecular techniques, including FRET-based imaging for calcium signals, to further this research. Mathematical modelling of calcium handling is also used in our analysis.
Insulin 'Feedback' Signalling in Type 1 and Type 2 Diabetes
Insulin is both a metabolic hormone and growth factor. The signal transduction cascades activated by insulin have been well studied in 'insulin target tissues' such as muscle and fat. However, many studies have revealed unexpected tissues where blocking insulin signalling has adverse consequences to glucose homeostasis. Surprisingly, along with the liver and brain, these studies show that the pancreatic beta-cell itself an important site of insulin action. In addition, islets from human type 2 diabetics appear to be 'insulin resistant'. We have investigated the role and mechanism of insulin signalling in the beta-cell and we have uncovered exciting differences compared to other tissues. We are continuing to study the effects of insulin on primary human and mouse islets, focusing on the anti-apoptotic effects of insulin and the mechanism of these effects. We have focused on signalling pathways regulated by the Raf-1 kinase and related proteins. We are testing the hypothesis that altered insulin expression plays a role in type 1 diabetes. This project is supported by grants from the Juvenile Diabetes Research Foundation.
Screening for Molecules that Promote Beta-Cell Survival
Virtually any cure for type 1 diabetes will require strategies to protect beta-cells from death and dysfunction. Many groups, including the our laboratory, have made progress in the past decade unraveling the molecular mechanisms and local factors that control pancreatic beta-cell survival and function. With recent support from JDRF, they have generated novel imaging technologies that allow for the first time the simultaneous, real-time analysis beta-cell function and programmed cell death, on a single-cell basis. At the same time, using bioinformatics and genomics, our laboratory has compiled and published a list of 234 locally produced secreted factors and 233 secreted factor receptors. High-throughput screening approaches now make it possible to examine simultaneously all of these potential survival and differentiation factors under multiple conditions related to the pathogenesis of type 1 diabetes. The overall goal of the proposed study is to identify the most powerful locally acting survival and/or differentiation factors in human islets. Such a factor could be harnessed to improve graft survival in clinical islet transplantation, improve the production surrogate beta-cells, and eventually treat patients with type 1 diabetes and/or their at-risk family members.
High-Throughput Screening for Molecules that Regulate Beta-Cell Differentiation Status
A major goal of regenerative medicine is the generation of fully functional pancreatic beta-cells, either from residual beta-cells in the patient or from stem cells. Both of these therapeutic avenues require a thorough understanding of the process by which beta-cells go from being immature to fully functional beta-cells. With SCN support, we devised a method to examine the maturation of single beta-cells for the first time using powerful custom microscopes and state-of-the-art fluorescent markers. At the same time, we have built (using CFI funds) the infrastructure to perform these experiments in a massively parallel manner. In doing so, we have become one of Canada's leading centres for image-based screening in the diabetes field. Here, Dr. Johnson proposes a simple extension of their previous 3-parameter, high-content, high-throughput screen to search for drugs that can accelerate beta-cell maturation. This new approach will place fluorescent markers in different parts of the cell, allowing for simultaneous readout of many more parameters, coined ultra-high-content screening.
Hyperinsulinemia as a Causal Factor in Obesity
The epidemics of obesity, type 2 diabetes and related diseases threaten to overrun the global healthcare system. We know that obesity, insulin resistance, early type 2 diabetes are all highly correlated with each other and are all associated with a higher than normal release of insulin from the pancreas, but we still do not fully understand the causal relationship between these phenomena. The most commonly accepted view is that obesity first leads to insulin resistance, which then leads to a compensatory hypersecretion of insulin, which finally results in diabetes when insulin release from the pancreas fail to meet demands. However, these implied cause and effect relationships have been questioned and are impossible to formally test in humans using rigorous genetic loss-of-function approaches. Indeed, there has long been evidence that basal insulin hypersecretion can precede insulin resistance and even obesity and clinical studies have also pointed to anti-obesity effects of drugs that block insulin secretion. We are testing the hypothesis that pancreatic insulin causes obesity directly, by genetically eliminating half of the insulin gene from the pancreas. We expect our study to have an important impact on our fundamental understanding of obesity, which might change the way we diagnose and treat millions of people.
Hyperinsulinemia and Insulin Signalling in Pancreatic Cancer
Pancreatic adenocarcinoma is the fourth most common cause of cancer death in Canada, but receives the lowest proportion of research funding of any major cancer. As a result, our understanding of the factors that initiate and drive the progression of this disease remains poor relative to our knowledge pertaining to other cancers. Diabetes mellitus and obesity are emerging as important risk factors for pancreatic cancer and the rapid rise in BMI foreshadows a rise in pancreatic cancer. Elevated insulin levels are a feature of both obesity and type 2 diabetes. Hyperinsulinemia has been investigated as a possible contributor to cancer initiation and progression. Lowering hyperinsulinemia with metformin was shown to reduce the risk of pancreatic cancer by 60%. Groups in Europe created headlines worldwide by showing an increased risk of cancer with use of long-acting insulin analogues. The question of whether elevated insulin can be a causal in the pathogenesis of pancreatic cancer has not been rigorously tested. To test this hypothesis, we have established models engineered to lack multiple alleles of their two Insulin genes. Mice with two of four Insulin alleles are hyperinsulinemic on a high-fat diet, whereas mice lacking all but one Insulin allele are hypoinsulinemic but not diabetic. We also have mouse models that will allow us to test whether genes involved in insulin-stimulated proliferation and anti-apoptosis in pancreatic islets, Raf-1, Akt or Pdx-1, participate in pancreatic cancer. Whether insulin signalling might synergize with Kras, the most frequently mutated gene in pancreatic cancer, is a key unanswered question. The overall goal is to test the hypothesis that hyperinsulinemia in diabetes can contribute to hyperproliferation in the exocrine pancreas, promote pre-cancerous lesions, and promote the survival of pancreatic cancer cells. We will also test the hypothesis that Raf-1, Akt and Pdx-1 are critical for insulin action in the pancreas. Together, these studies have the potential to increase our understanding of this devastating disease and increase avenues towards rational therapeutic intervention. This information will eventually be used to identify novel compounds capable of blocking the hyperproliferative and anti-apoptotic effects of insulin in primary human pancreatic tissue and pancreatic tumor cell lines.
New Roles for RyR2-Mediated Calcium Flux in Cardiomyocyte Survival, Metabolism
Every heartbeat is composed of a complex cycle of highly orchestrated events. The cardiac ryanodine receptor calcium channel (RyR2) is central to this cycle, releasing calcium to cause heart muscle cell contraction with each heartbeat. Diseases such as arrhythmias and diabetic cardiomyopathy are associated with changes in RyR2 function. However, it has remained unclear whether the other cellular symptoms of these conditions are causes or consequences of the loss of RyR2 function. Working in other cell types, we have recently described unexpected roles for RyR2, namely the control of gene expression and cell survival. In this project we examine hearts with selective deletion of RyR2 calcium channels and determine which cellular functions are changed most directly as a result. These studies will provide new insight into the dysfunction and death of heart cells in disease. |
67. Kruit JK, Wijesekara N, Manning Fox JE, Dai X-Q, Brunham LR, Searle GJ, Morgan GP, Costin AJ, Tang R, Johnson JD, Light PE, Marsh BJ, MacDonald PE, Verchere CB, Hayden MR. Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules. Accepted in Diabetes Sept. 2, 2011.
66. Chu KY, Li H, Wada K, Johnson JD. Ubiquitin C-terminal hydrolase L1 is required for β-cell survival and function in lipotoxicity. Accepted in Diabetologia August 31, 2011.
65. Alejandro EU, Lim GE, Mehran AE, Hu X, Taghizadeh F, Pelipeychenko D, Baccarini M, Johnson JD. Pancreatic beta-cell Raf-1 is required for glucose tolerance, insulin secretion and insulin 2 transcription. FASEB J Epub August 4, 2011.
64. Szabat M, Pourghaderi P, Soukhatcheva G, Verchere CB, Warnock GL, Piret JM, Johnson JD. Kinetics and genomic profiling of adult human and mouse β-cell maturation. Accepted in Islets April 19, 2011. Volume 3, Issue 4 July/August 2011. Pages 175 – 187.
63. Chu KY, Briggs MJL, Albrecht T, Drain PF, Johnson JD. Differential regulation and localization of carboxypeptidase D and carboxypeptidase E in human and mouse β-cells. Accepted in Islets April 7, 2011. Volume 3, Issue 4 July/August 2011. Pages 155 – 165.
62. Gallo M, Park D, Luciani DS, Kida K, Palmieri F, Blacque OE, Johnson JD, Riddle DL. MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion. Accepted in PLoS ONE February 15, 2011.
61. Johnson JD, Bround M, White SA, Luciani DS. Nanospaces between endoplasmic reticulum and mitochondria as control centers of pancreatic β-cell metabolism and survival. Invited Review. In press, Protoplasma.
60. Fu M, Li L, Albrecht T, Johnson JD, Kojic LD, Nabi IR. Autocrine molility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release. Cell Death and Differentiation. Accepted November 30, 2010. Epub Jan 21, 2011.
59. Yang YHC, Szabat M, Bragagnini C, Kott K, Helgason CD, Hoffman BG, Johnson JD. Paracrine signaling loops in adult pancreatic islets: Netrins modulate beta-cell apoptosis via Neogenin and Unc5a. Accepted in Diabetologia November 8, 2010. EPub Jan 7, 2011.
58. Hoesli CA, Raghuram K, Kiang R, Mocinecová D, Hu X, Johnson JD, Lacík I, Kieffer TJ, Piret JM. 2010. Pancreatic Cell Immobilization in Alginate Beads Produced by Emulsion and Internal Gelation. EPub Oct 11, 2010. Biotechnology & Bioengineering.
57. Hill JA, Szabat M, Hoesli CA, Gage BK, Yang YH, Williams DE, Riedel MJ, Luciani DS, Kalynyak TB, Tsai K, Ao Z, Andersen RJ, Warnock GL, Piret JM, Kieffer TJ, Johnson JD. 2010. Multi-parameter, high-content, high-throughput screening for regulators of beta-cell fate and function. Accepted in PLoS One September 2, 2010. Sep 23;5(9):e12958.
56. Chu KY, Lin Y, Hendel A, Kulpa JE, Brownsey RW, Johnson JD. ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta-cells. Journal of Biological Chemistry. EPub. August 7, 2010. Oct 15;285(42):32606-15.
55. Bernal-Mizrachi E, Cras-Méneur C, Johnson JD, Permutt MA. 2010 Transgenic overexpression of active calcineurin in beta-cells results in decreased beta-cell mass and hyperglycemia in mice. PLos ONE. Aug 3;5(8):e11969.
54. Szabat, M, Johnson, JD, Piret JM. 2010. Reciprocal modulation of adult beta-cell maturity by activin A and follistatin. Diabetologia. 53: 1680-9. Epub 2010 May 4.
53. Wang F, Wang Y, Kim M, Puthanveetil P, Ghosh S, Luciani DS, Johnson JD, Abrahani A, Rodrigues B. 2010. Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization. Diabetes, 87:127-36. Epub 2010 Feb 17.
52. Hutton MJH, Soukhatcheva G, Johnson JD, Verchere CB. Role of the TLR signalling molecule TRIF in beta-cell function and glucose homeostasis. Islets. Accepted January 14, 2010.
51. Alejandro EU, Kalynyak TB, Taghizadeh T, Gwiazda KS, Rawstrom EK, Jacob KJ, Johnson JD. 2010. Insulin activates Erk via Raf-1 and NAADP-dependent calcium signals in pancreatic beta-cells. Endocrinology. Epub Jan 7, 2010. 151(2):502-12.
50. Fujimoto K, Hanson PT, Tran H, Ford EL, Han Z, Johnson JD, Levine B, Schimdt B, Wice BM, Polonsky KS. 2009. Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation. Journal of Biological Chemistry. Oct 2;284(40):27664-73. Epub 2009 Aug 4.
49. Johnson JD, Otani K, Bell GI, Polonsky KS. 2009. Impaired insulin exocytosis in transgenic mice over-expressing calpastatin in pancreatic beta-cells. lslets August 4, 2009.
48. Kewalramani G, Puthanveetil P, Wang F, Kim MS, Deppe S, Abrahani A, Luciani DS, Johnson JD, Rodrigues B. 2009. AMP-activated protein kinase confers protection against TNF-alpha induced cardiac cell death. Cardiovascular Research. Epub June 12, 2009. 84, 42-53.
47. Li J, Johnson JD. 2009. Mathematical models of subcutaneous injection of insulin analogues: A mini-review. Discrete and Continuous Dynamical Systems – Series B. Accepted May 2. 12: 401-414.
46. Johnson JD, Ao Z, Ao P, Li H, Dai L, He Z, Tee M, Potter KJ, Meloche RM, Thompson DM, Verchere CB, Warnock GL. 2009. Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplantation. Epub April 10, 2009. 18: 833-845.
45. Gwiazda K, Yang TB, Lin Y, Johnson JD. 2009. Effects of palmitate on ER and cytosolic Ca2+ homeostasis in b-cells. American Journal of Physiology. Accepted Jan 10, 2009. 296: E690-E701.
44. Szabat M, Luciani DS, Piret J, Johnson JD. 2008. Maturation of adult beta-cells revealed using a Pdx1/Insulin dual reporter lentivirus. Endocrinology. Epub December 3, 2008. 150: 1627-1635.
43. Warnock GL, Thompson DM, Meloche RM, Shapiro RJ, Ao Z, Keown P, Johnson JD, Verchere CB, Partovi N, Begg IS, Fung M, Kozak SE, Tong SO, Al Ghofaili KM, Harris C. 2008. A Multi-Year Analysis of Islet Transplantation Compared With Intensive Medical Therapy on Progression of Complications in Type 1 Diabetes. Transplantation. 86(12):1762-6.
42. Luciani DS, Gwiazda K, Yang TL, Kalynyak TB, Bychkivska Y, Jeffrey KD, Frey MHZ, Sampaio AV, Underhill TM, Johnson JD. 2008. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and b-cell death. Diabetes. E-pub. Nov 27, 2008. 58(2):422-32.
41. Johnson JD. 2008. Proteomic identification of carboxypeptidase E connects lipid-induced beta-cell apoptosis and dysfunction in type 2 diabetes. Invited review for Cell Cycle. Jan 1;8(1):38-42. Epub 2009 Jan 4.
40. Alejandro EU, Johnson JD. 2008. Raf-1 kinase in the pancreatic beta-cell. CellSciences. Published Online Oct 2008. Invited review.
39. Chang JP, Johnson JD, Sawisky GR, Grey CL, Mitchell G, Booth M, Volk MM, Parks SK, Thomson E, Goss GG, Klausen C, Habibi HR. 2009. Signal transduction in multifactorial neuroendocrine control of gonadotropin secretion and synthesis in teleosts – studies on the goldfish model. (Invited Review) General and Comparative Endocrinology. E-pub Sept 21. Mar;161(1):42-52.
38. Walia P, Asadi A, Kieffer TJ, Johnson JD, Chanoine J-P. 2009. Ontogeny of ghrelin, obestatin, preproghrelin, and prohormone convertases in rat pancreas and stomach. Pediatric Research. E-pub Sept 3. Jan;65(1):39-44.
37. Wang Y, Huang B, Luciani DS, Wang X, Johnson JD, Proud CG. 2008. Rheb activates protein synthesis and growth in adult rat cardiomyocytes. Journal of Molecular and Cellular Cardiology. 45: 812-20. Epub 2008 Aug 3.
36. Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD. 2008. Carboxypeptidase E mediates palmitate-induced beta-cell ER-stress and apoptosis. Proc. Natl. Acad. Sci. USA. (Track II). Jun 17;105(24):8452-7. Epub 2008 Jun 11.
35. Johnson JD, Alejandro EU. 2008. Control of Pancreatic Beta-cell Fate by Insulin Signaling: The Sweet Spot Hypothesis. Cell Cycle. Invited review. EPub. March 3, 2008. May 15;7(10):1343-7.
34. Dror V, Kalynyak TB, Bychkivska Y, Frey MHZ, Tee M, Jeffrey KD, Nguyen V, Luciani DS, Johnson JD. 2008. Glucose and ER channels regulate HIF1b via presenilin1 in pancreatic b-cells. Journal of Biological Chemistry. EPub Jan 4, 2008. 283:9909-16.
33. Beith JL, Alejandro EU, Johnson JD. 2008. Insulin stimulates primary β-cell proliferation via raf-1 kinase. Endocrinology. 149:2251-60.
32. Alejandro EU, Johnson JD. 2008. Inhibition of Raf-1 alters multiple downstream pathways to induce pancreatic b-cell apoptosis. Journal of Biological Chemistry. Jan 25;283(4):2407-17. Epub 2007 Nov 15.
31. Dror V, Nguyen V, Walia P, Kalynyak TB, Hill JA, Johnson JD. 2007. Notch signalling suppresses apoptosis in adult pancreatic islet cells. Diabetologia 50:2504-15.
30. Luciani DS, Ao P, Hu X, Warnock GL, Johnson JD. 2007. Voltage-gated Ca2+ influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na+/Ca2+ exchange inhibitor CGP-37157. European Journal of Pharmacology. 576:18-25.
29. Warnock GL, Liao T, Wang X, Ou D, Ao Z, Johnson JD, Verchere CB, Thompson D. 2007. An Odyssey of Islet Transplantation for Therapy of Type 1 Diabetes. World Journal of Surgery. Aug;31(8):1569-76. Epub 2007 Jun 12.
28. Johnson JD. 2007. Pancreatic β-cell apoptosis in maturity onset diabetes of the young. (Invited review). Canadian Journal of Diabetes. 31:67-74.
27. Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Johnson JD, Parks JS, Verchere CB, Hayden MR. 2007. ß-Cell ABCA1 Influences Insulin Secretion, Glucose Homeostasis and Response to Thiazolidinedione Treatment. Nature Medicine. 13: 230-7. Published online February 18.
26. Johnson JD, Bernal-Mizrachi E, Alejandro E, Han Z, Kalynyak T, Li H, Beith JL, Gross J, Warnock GL, Townsend RR, Permutt MA, Polonsky KS. 2006. Insulin protects islets from apoptosis via pdx-1 and specific changes in the human islet proteome. Proc. Natl. Acad. Sci. USA. (Track II).103: 19575-80.
25. Johnson JD, Bernal-Mizrachi E, Ford EL, Han Z, Kusser KL, Luciani DS, Tran H, Randall TD, Lund FE, Polonsky KS. 2006. Suppressed insulin signaling and increased apoptosis in Cd38 null islets. Diabetes. 55: 2737-2746.
24. Wideman RD, Yu ILY, Webber TD, C. Verchere CB, Johnson JD, Cheung AT, Kieffer TJ. 2006. Improving Function and Survival of Pancreatic Islets by Endogenous Production of GLP-1. Proc. Natl. Acad. Sci. USA. (Track II). 103: 13468–13473.
23. Luciani DS, Johnson JD. 2005. Acute effects of insulin on dispersed cells from transplantable human islets. Molecular and Cellular Endocrinology. 241: 88-98.
22. Warnock GL, Meloche RM, Thompson D, Shapiro J, Fung M, Ao Z, Ho S, He Z, Dai LJ, Young L, Blackburn L, Kozak S, Kim P, Al-Adra D, Johnson JD, Liao T, Elliott T, Verchere CB. 2005. Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. Archives of Surgery. 140:735-44.
21. Johnson JD, Chang JP. 2005. Calcium buffering activity of mitochondria controls basal growth hormone secretion and modulates specific neuropeptide signaling. Cell Calcium. 37:573-81.
20. Ohsugi M, Cras-Méneur C, Zhou Y, Bernal-Mizrachi E, Johnson JD, Luciani DS, Polonsky KS, Permutt MA. 2005. Reduced expression of the insulin receptor in mouse insulinoma (MIN6) cells reveals multiple roles of insulin signaling in gene expression, proliferation, insulin content and secretion. Journal of Biological Chemistry. 280, 4992-5003.
19. Bernal E, Fatrai S, Johnson JD, Ohsugi M, Otani K, Han Z, Polonsky KS, Permutt MA. 2004. Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced AKT activity in pancreatic islet beta-cells. Journal of Clinical Investigation. 114: 928-936.
18. Johnson JD, Han Z, Otani K, Ye H, Zhang Y, Wu H, Horikawa Y, Misler S, Bell GI, Polonsky KS. 2004. RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. Journal of Biological Chemistry 279: 24794-24802.
17. Johnson JD, Kuang S, Misler S, Polonsky KS. 2004. Ryanodine receptors in human pancreatic beta-cells: Localization and effects on insulin secretion. FASEB J. 10.1096/fj.03-1280fje.
16. Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, Misler S, Edlund H, Polonsky KS. 2003. Increased islet apoptosis in PDX-1+/- mice. Journal of Clinical Investigation. 111:1147-1160.
15. Koster JC, Remedi M, Flagg T, Johnson JD, Markova K, Marshall BA, Nichols CG. 2002. Targeted Suppression of b-cell KATP Channels Induces Persistent Hyperinsulinism. Proc. Natl. Acad. Sci. USA. (Track II). 99:16992-7.
14. Johnson JD, Klausen C, Habibi HR, Chang JP. 2003. A GnRH-insensitive, thapsigargin-sensitive Ca2+ store reduces basal gonadotropin exocytosis and gene expression: Comparison with agonist-sensitive Ca2+ stores. J Neuroendocrinology 15:204-14.
13. Johnson, JD, Misler S. 2002. Nicotinic acid adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human b-cells. Proc. Natl. Acad. Sci. USA (Track II). 99: 14566-14571.
12. Johnson JD, Chang JP. 2002. Agonist-specific and sexual stage-dependent inhibition of GnRH-stimulated gonadotropin and growth hormone release by ryanodine: Relationship to sexual stage-dependent caffeine-sensitive hormone release. J Neuroendocrinology 14: 144-155.
11. Johnson JD, Klausen C, Habibi HR, Chang JP. 2002. Function-specific Ca2+ stores selectively regulate growth hormone secretion, storage and mRNA. Am J Physiol. Endo. 282: E810-E819.
10. Johnson JD, Wong CJH, Yunker WK, Chang JP. 2001. Caffeine stimulated GTH-II release involves Ca2+ stores with novel properties. Am J Physiol. Cell 282: C635-C645.
9. Wong CJH, Kwong P, Johnson JD, Yunker WK, Chang JP. 2001. Modulation of GTH-II release by K+ channel blockers in goldfish gonadotropes: a novel stimulatory action of 4-aminopyridine J Neuroendocrinol.13: 915-958.
8. Chang JP, Wirachowsky NR, Kwong P, Johnson JD. 2001. PACAP stimulation of gonadotropin-II secretion in goldfish pituitary cells: mechanisms of action and interaction with gonadotropin-releasing hormone. J Neuroendocrinology, 13: 540-550.
7. Wong CJH, Johnson JD, Yunker WK, Chang JP. 2001. Caffeine stores and dopamine differentially require Ca2+ channels to stimulate hormone secretion. Am J Physiol Integrative 280: R494-R503.
6. Wirachowsky NR, Kwong P, Yunker WK, Johnson JD, Chang JP. 2000. Mechanisms of action of pituitary adenylate cyclase-activating polypeptide (PACAP) on growth hormone release from dispersed goldfish pituitary cells. Fish Physiology Biochemistry 23: 201-214.
5. Johnson JD, Van Goor F, Jobin, RM, Wong CJH, Chang JP. 2000. Agonist-specific Ca2+ signaling systems, composed of multiple intracellular Ca2+ stores, regulate gonadotropin secretion. Molecular and Cellular Endocrinology 170: 15-29.
4. Johnson, JD, Chang, JP. 2000. Novel, thapsigargin-insensitive intracellular Ca2+ stores control growth hormone release from goldfish pituitary cells. Molecular and Cellular Endocrinology. 165: 139-150.
3. Chang JP, Johnson JD, Van Goor F, Wong CJH, Yunker WK, Uretsky AD, Jobin RM, Wong AOL, Goldberg JI. 2000. Signal transduction mechanisms mediating secretion in goldfish gonadotropes and somatotropes. Biochemistry and Cell Biology. 78: 139-153.
2. Johnson JD, Chang JP. 2000. Function- and agonist-specific Ca2+ signalling: the requirement for and mechanism of spatial and temporal complexity in Ca2+ signals. Biochemistry & Cell Biology 78: 217-240.
1. Johnson JD, Van Goor F, Wong CJH, Goldberg JI, Chang JP. 1999. Two endogenous gonadotropin-releasing hormones generate dissimilar Ca2+ signals in identified goldfish gonadotropes. General & Comparative Endocrinology. 116: 178-191. |
Dr Connie Chu
Dr Gareth Lim
Dr Marta Szabat
Carol Yang
Arya Mehran
Tobias Albrecht
Nicole Templeman |
(PostDoctoral Fellow, Sept 2008-)
(PostDoctoral Fellow, Sept 2009-)
(PostDoctoral Fellow, Sept 2010-)
(PhD Student, Sept 2008-)
(PhD Student, Sept 2008-)
(PhD Student, Sept 2009-)
(PhD Student, Sept 2011-)
|
Michelle Chan
Michael Bround
Sarah White
(co-supervised)
Nardin Moniri
Saba Marzara
Micah Piske |
(MSc Student, Sept 2010-)
(MSc Student, Sept 2010-)
(MSc Student, Sept 2010-)
(Undergraduate Student, Sept 2010-)
(Undergraduate Student, May 2010-)
(Undergraduate Student, Sept 2011-) |
The Laboratory for Molecular Signalling in Diabetes is looking for exceptional students and post-doctoral fellows.
Potential applicants should be highly motivated. Potential students should have a strong interest in pursuing a career in research and be competitive for external scholarships. Post-doctoral applicants should have experience in a relevant research area, a strong publication record and be competitive for external fellowship awards.
Please contact Dr. Johnson directly by e-mail if you are interested. Include a curriculum vitae (with grades for students), a statement of career goals, and an outline of the specific research you see yourself doing in the lab.
|
|
|
|
