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Dan S Luciani
PhD

Investigator, BC Children's Hospital

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.

Academic Affiliations

  • Associate Professor, , Department of Surgery, Faculty of Medicine, University of British Columbia
  • Research Theme: Childhood Diseases
  • Research Group(s): Diabetes

Contact Information

Location

950 West 28th Ave, Vancouver, BC, Canada, V5Z 4H4

(604) 875-2000 ext. 6170

dluciani@bcchr.ca

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 / 2023

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic -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 / 2022

The role of mitochondrial apoptotic pathway in islet amyloid-induced -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 / 2021

Bcl-xL restricts transcriptional, morphological and functional decompensation of -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 / 2021

Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic -cells under glucolipotoxic stress.

Scientific reports

DOI: 10.1038/s41598-020-67755-3 PubMed: 32620813

07 / 2020

A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic -cells

American Journal of Physiology-Endocrinology and Metabolism

Ahsen Chaudhry and Rocky Shi and Dan S. Luciani

DOI: 10.1152/ajpendo.00457.2019

02 / 2020

Bcl-2 Regulates Reactive Oxygen Species Signaling and a Redox-Sensitive Mitochondrial Proton Leak in Mouse Pancreatic -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 / 2016

Alloantigen-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 / 2016

Myt3 Mediates Laminin-V/Integrin-1-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 / 2015

B7-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 / 2014

Control 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 / 2014

Complex patterns of metabolic and Ca 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 / 2013

Cardiomyocyte 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 / 2013

Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic -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 / 2013

Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic -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 / 2012

MISC-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

Glucose-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 / 2010

A 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

Mechanisms 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

AMP-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 / 2009

Maturation 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 / 2009

Roles 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 / 2009

Pancreatic Beta-cell Apoptosis

Modern Insights Into Disease From Molecules to Man: APOPTOSIS.

Rheb 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 / 2008

Carboxypeptidase 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 / 2008

Glucose 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 / 2008

Voltage-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 / 2007

Interaction 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 / 2007

A 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 / 2006

Suppressed 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 / 2006

Ca2+ 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 / 2006

Acute 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 / 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.

Ohsugi M and Cras-Mneur 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 / 2005

Increased 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

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 & Awards

Juvenile 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

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