Congratulations to the BC Children's Hospital Research Institute (BCCHR) and Women’s Health Research Institute (WHRI) investigators and their teams who were awarded funding through the Canadian Institutes of Health Research (CIHR) Fall 2021 Project Grant competition. Our research community received around $6 million in new research grants as principal investigators or co-investigators.
- Overview
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Diabetes develops when the pancreas does not release enough insulin to lower blood sugar (glucose) levels after a meal. This happens when the insulin producing ß-cells in the pancreas are defective or if the number of ß-cells is reduced. Accordingly, functional failure and ‘cellular suicide’ of ß-cells promote both type 1 and type 2 diabetes. Moreover, the effectiveness of islet transplantation as a treatment for type 1 diabetes is limited by ß-cell death both before and after transplantation.
Our research group seeks to clarify the complex mechanisms that link ß-cell function, ß-cell failure and various pathways of ß-cell death. Intriguing new findings, including our own recent studies, suggest that the cellular machinery that mediates cell ‘suicide’ also has important roles in normal ß-cell function and can control if ß-cells adapt or fail during the cellular stress associated with diabetes. We study these mechanisms from the level of genetic changes to the impact of these on single cell function and the progression of diabetes. In this way we hope to identify and characterize new targets for diabetes prevention and therapy.
- Publications
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Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice
Diabetologia
Ben Vanderkruk and Nina Maeshima and Daniel J. Pasula and Meilin An and Cassandra L. McDonald and Priya Suresh and Dan S. Luciani and Francis C. Lynn and Brad G. Hoffman
DOI: 10.1007/s00125-023-05896-6
06/2023Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic ß-cell proliferation via phosphorylation of HDAC5 in mice
Shugo Sasaki and Cuilan Nian and Eric E. Xu and Daniel J. Pasula and Helena Winata and Sanya Grover and Dan S. Luciani and Francis C. Lynn
DOI: 10.1101/2022.12.23.521810
12/2022The role of mitochondrial apoptotic pathway in islet amyloid-induced ß-cell death
Molecular and Cellular Endocrinology
Helen Y. Wong and Queenie Hui and Zhenyue Hao and Garth L. Warnock and Minna Woo and Dan S. Luciani and Lucy Marzban
DOI: 10.1016/j.mce.2021.111424
11/2021Bcl-xL restricts transcriptional, morphological and functional decompensation of ß-cell mitochondria under chronic glucose excess
Daniel J. Pasula and Rocky Shi and Ben Vanderkruk and Alexis Z.L. Shih and Yuanjie Zou and Ahsen Chaudhry and Brad G. Hoffman and Dan S. Luciani
DOI: 10.1101/2021.10.25.465491
10/2021Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic ß-cells under glucolipotoxic stress.
Scientific reports
DOI: 10.1038/s41598-020-67755-3
PubMed: 32620813
07/2020A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic ß-cells
American Journal of Physiology-Endocrinology and Metabolism
Ahsen Chaudhry and Rocky Shi and Dan S. Luciani
DOI: 10.1152/ajpendo.00457.2019
02/2020Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic ß-Cells.
Aharoni-Simon M and Shumiatcher R and Yeung A and Shih AZ and Dolinsky VW and Doucette CA and Luciani DS
DOI: 10.1210/en.2015-1964
PubMed: 27070098
06/2016Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor.
MacDonald KG and Hoeppli RE and Huang Q and Gillies J and Luciani DS and Orban PC and Broady R and Levings MK
DOI: 10.1172/JCI82771
PubMed: 26999600
04/2016Myt3 Mediates Laminin-V/Integrin-ß1-Induced Islet-Cell Migration via Tgfbi.
Tennant BR and Chen J and Shih AZ and Luciani DS and Hoffman BG
DOI: 10.1210/ME.2014-1387
PubMed: 26177052
09/2015B7-H4 as a protective shield for pancreatic islet beta cells.
Sun AC and Ou D and Luciani DS and Warnock GL
DOI: 10.4239/wjd.v5.i6.739
PubMed: 25512776
12/2014Control of insulin secretion by cytochrome C and calcium signaling in islets with impaired metabolism.
Rountree AM and Neal AS and Lisowski M and Rizzo N and Radtke J and White S and Luciani DS and Kim F and Hampe CS and Sweet IR
DOI: 10.1074/jbc.M114.556050
PubMed: 24841202
07/2014Complex patterns of metabolic and Ca²¿ entrainment in pancreatic islets by oscillatory glucose.
Pedersen MG and Mosekilde E and Polonsky KS and Luciani DS
DOI: 10.1016/j.bpj.2013.05.036
PubMed: 23823221
07/2013Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo.
Bround MJ and Wambolt R and Luciani DS and Kulpa JE and Rodrigues B and Brownsey RW and Allard MF and Johnson JD
DOI: 10.1074/jbc.M112.427062
PubMed: 23678000
06/2013Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells.
Luciani DS and White SA and Widenmaier SB and Saran VV and Taghizadeh F and Hu X and Allard MF and Johnson JD
DOI: 10.2337/db11-1464
PubMed: 22933114
01/2013Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic ß-cell metabolism and survival.
Johnson JD and Bround MJ and White SA and Luciani DS
DOI: 10.1007/s00709-011-0349-3
PubMed: 22105567
02/2012MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion.
Gallo M and Park D and Luciani DS and Kida K and Palmieri F and Blacque OE and Johnson JD and Riddle DL
DOI: 10.1371/journal.pone.0017827
PubMed: 21448454
2011Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization.
Wang F and Wang Y and Kim MS and Puthanveetil P and Ghosh S and Luciani DS and Johnson JD and Abrahani A and Rodrigues B
DOI: 10.1093/cvr/cvq051
PubMed: 20164120
07/2010A multi-parameter, high-content, high-throughput screening platform to identify natural compounds that modulate insulin and Pdx1 expression.
Hill JA and Szabat M and Hoesli CA and Gage BK and Yang YH and Williams DE and Riedel MJ and Luciani DS and Kalynyak TB and Tsai K and Ao Z and Andersen RJ and Warnock GL and Piret JM and Kieffer TJ and Johnson JD
DOI: 10.1371/journal.pone.0012958
PubMed: 20886041
2010Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies.
Johnson JD and Luciani DS
DOI: 10.1007/978-90-481-3271-3_19
PubMed: 20217509
2010AMP-activated protein kinase confers protection against TNF-{alpha}-induced cardiac cell death.
Kewalramani G and Puthanveetil P and Wang F and Kim MS and Deppe S and Abrahani A and Luciani DS and Johnson JD and Rodrigues B
DOI: 10.1093/cvr/cvp166
PubMed: 19477967
10/2009Maturation of adult beta-cells revealed using a Pdx1/insulin dual-reporter lentivirus.
Szabat M and Luciani DS and Piret JM and Johnson JD
DOI: 10.1210/en.2008-1224
PubMed: 19095744
04/2009Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death.
Luciani DS and Gwiazda KS and Yang TL and Kalynyak TB and Bychkivska Y and Frey MH and Jeffrey KD and Sampaio AV and Underhill TM and Johnson JD
DOI: 10.2337/db07-1762
PubMed: 19033399
02/2009Pancreatic Beta-cell Apoptosis
Modern Insights Into Disease From Molecules to Man: APOPTOSIS.
2009Rheb activates protein synthesis and growth in adult rat ventricular cardiomyocytes.
Wang Y and Huang BP and Luciani DS and Wang X and Johnson JD and Proud CG
DOI: 10.1016/j.yjmcc.2008.07.016
PubMed: 18722381
12/2008Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.
Jeffrey KD and Alejandro EU and Luciani DS and Kalynyak TB and Hu X and Li H and Lin Y and Townsend RR and Polonsky KS and Johnson JD
DOI: 10.1073/pnas.0711232105
PubMed: 18550819
06/2008Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells.
Dror V and Kalynyak TB and Bychkivska Y and Frey MH and Tee M and Jeffrey KD and Nguyen V and Luciani DS and Johnson JD
DOI: 10.1074/jbc.M710601200
PubMed: 18174159
04/2008Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157.
Luciani DS and Ao P and Hu X and Warnock GL and Johnson JD
DOI: 10.1016/j.ejphar.2007.07.055
PubMed: 17719029
12/2007Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets.
Bertram R and Satin LS and Pedersen MG and Luciani DS and Sherman A
DOI: 10.1529/biophysj.106.097154
PubMed: 17172305
03/2007A simplified model for mitochondrial ATP production.
Bertram R and Gram Pedersen M and Luciani DS and Sherman A
DOI: 10.1016/j.jtbi.2006.07.019
PubMed: 16945388
12/2006Suppressed insulin signaling and increased apoptosis in CD38-null islets.
Johnson JD and Ford EL and Bernal-Mizrachi E and Kusser KL and Luciani DS and Han Z and Tran H and Randall TD and Lund FE and Polonsky KS
DOI: 10.2337/db05-1455
PubMed: 17003338
10/2006Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets.
Luciani DS and Misler S and Polonsky KS
DOI: 10.1113/jphysiol.2005.101766
PubMed: 16455690
04/2006Acute effects of insulin on beta-cells from transplantable human islets.
Luciani DS and Johnson JD
DOI: 10.1016/j.mce.2005.06.006
PubMed: 16099589
09/2005Reduced expression of the insulin receptor in mouse insulinoma (MIN6) cells reveals multiple roles of insulin signaling in gene expression, proliferation, insulin content, and secretion.
Ohsugi M and Cras-Méneur C and Zhou Y and Bernal-Mizrachi E and Johnson JD and Luciani DS and Polonsky KS and Permutt MA
DOI: 10.1074/jbc.M411727200
PubMed: 15546857
02/2005Increased islet apoptosis in Pdx1+/- mice.
Johnson JD and Ahmed NT and Luciani DS and Han Z and Tran H and Fujita J and Misler S and Edlund H and Polonsky KS
DOI: 10.1172/JCI200316537
PubMed: 12697734
04/2003 - Research
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Control of ß-cell mitochondrial dynamics, function and failure by anti-apoptosis proteins
Mitochondria are fascinating organelles that constantly undergo fusion and fission to form a complex and highly dynamic network. Their best known role is to act as the cell’s ‘powerhouse’ that generates ATP, and this process is absolutely essential for pancreatic ß-cells to secrete insulin in response to increases in blood glucose and other nutrients after a meal. However, if the levels of glucose and fatty acids in the blood become too high for long periods of time, it causes failure and loss of ß-cells, which is a major reason type 2 diabetes develops. Disruption of mitochondrial physiology appear to be a significant part of this, but how and why this happens is still poorly understood. Our research therefore aims to clarify the mechanisms of ß-cell mitochondrial (dys)function, and how it is connected to the fate of the ß-cells. As a major part of this work, we are investigating novel roles for a group of cell survival proteins, called the Bcl-2 family, in the control of ß-cell mitochondrial dynamics and health under nutrient stress.The importance of autophagy and lysosomes for ß-cell function and survival
Recent research has discovered that cells under stress often rely on a process called autophagy for continued function and survival. In autophagy, a stressed cell can remove damaged parts (for instance dysfunctional mitochondria) by delivering them to the cellular ‘garbage cans’ (lysosomes) for breakdown and recycling. It is known that failure of lysosomes, and of the overall autophagy recycling system, can cause serious diseases. Nonetheless, we still know very little about the importance of these processes in pancreatic ß-cells and diabetes. In our laboratory we use novel gene knockout models and advanced microscopy techniques to determine if disruption of this cellular garbage removal system contributes significantly to ß-cell stress, loss of insulin secretion and the development of diabetes. We are also investigating the importance of these processes for the ability of ß-cells to survive and continue functioning after they have been transplanted as a treatment for type 1 diabetes.Honours & AwardsJuvenile Diabetes Research Foundation (JDRF), Career Development Award, 2013-2018
Michael Smith Foundation for Health Research (MSFHR) Postdoctoral Fellowship, 2008-2009
Canadian Diabetes Association (CDA) Postdoctoral Fellowship, 2008-2009
Research Group MembersSarah Baghestani, Research assistant
Tien Do, Co-op Research Assistant
Joshua Jacob, Graduate Student
Mitsu Komba, Lab Tech , Lab Tech
Anjali Parthasarathy, Co-op Research Assistant
Daniel Pasula, Graduate Student
Terence Tam, Research Technician
Jana Thistle, Graduate Student
Alyssa Weinrauch, Postdoctoral Fellow
Yuanjie Zou, Doctoral Student , Doctoral Student
