Control of beta cell function and survival by RYR2-mediated calcium signals

Active Project Grant Awarded Last action

Award ID
R01DK127236
Recipient
Awarding agency
Obligated
$3,617,416

Award facts

Completion date 86% complete
Originally
Funding
  • $3,137,859.00 Federal
  • $479,557.00 Non-federal
Place of performance
Indianapolis, IN 46202, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Despite the importance of SS cell failure in the progression of diabetes (type 1, type 2, and multiple monogenic forms), the underlying molecular mechanisms responsible for SS cell dysfunction remain incompletely understood. Release of insulin from the pancreatic SS cell occurs in response to dynamic changes in cytosolic calcium (CA2+) levels. To date, the majority of studies of SS cell physiology have focused on the regulation of CA2+ influx via plasma membrane ION channels, which have traditionally been more amenable to study via electrophysiological approaches. These studies have supported a dominant role for katp channel-dependent plasma membrane depolarization and CA2+ influx via voltage-gated CA2+ channels in the regulation of insulin release, especially in response to very high concentrations of glucose. However, recent improvements in high temporal resolution imaging pioneered by our group have enabled the detection of robust CA2+ signals in SS cells stimulated with more physiologically relevant glucose concentrations, even in the absence of changes in plasma membrane potential, pointing to a critical role for the regulated release of CA2+ from intracellular stores. In support of this, our published and preliminary data show that pharmacological manipulation of the activity of intracellular ryanodine receptors (RYR) uniquely modulates these ultrafast CA2+ release events, even in voltage-clamp conditions, while also impacting glucose-stimulated insulin secretion. Together with other groups, we have found that the RYR2 isoform predominates in pancreatic SS cells, and importantly showed using QRT-PCR and mass spectometry-based proteomics that RYR2 mrna and protein can be identified in human and mouse islets and purified SS cells. Furthermore, our preliminary data indicate that mice with SS cell selective RYR2 knockout have reduced insulin secretion and glucose intolerance, while EX vivo studies suggest that ER CA2+ leak via dysregulated RYR activity leads to alterations in SS cell CA2+ signalling and accelerated SS cell death. Against this background, we hypothesize that RYR2 channels serve as critical rheostats of SS cell health and function and that they play key roles in diabetes progression. To test this hypothesis, we have assembled a multidisciplinary MPI team with expertise in SS cell biology, diabetes physiology, quantitative imaging, and disease modelling, and three specific aims are proposed. In specific aim 1, we will quantify SS cell RYR2 activity and roles in pancreatic slices and in vivo using intravital imaging. Specific aim 2 will determine the in vivo role of SS cell RYR2 in insulin secretion, SS cell survival, and glucose homeostasis using a highly SS cell-specific knockout mouse model. Specific aim 3 will utilize mass spectrometry to determine mechanisms underlying ER stress-induced RYR2 dysfunction and in vitro and in vivo mouse models to define how ER stress-induced RYR2 dysfunction impacts SS cell CA2+ signaling and survival.

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $419,637 $0
Amendment $403,201 $0
Amendment $449,903 $0
Amendment $453,002 $0
Amendment $453,002 $0
Amendment $479,557 $0
Original award $479,557 $479,557

Subawards

Subrecipient Amount Awarded
The University Of British Columbia The Johnson lab will utilize novel resources including a unique β cell-specific Ryr2 knockout mouse to test the hypothesis that the ryanodine receptor regulates… $81,989
Universitaet Wien For the proposal “Control of beta cell function and survival by RYR2-mediated calcium signals”, the Medical University of Vienna (MUW), via its Center for… $51,993

Quick answers

Who received award R01DK127236?

R01DK127236 was awarded to Trustees Of Indiana University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 20, 2021.

How much is award R01DK127236 worth?

$3,617,416 has been obligated on R01DK127236: $3,137,859 in federal funding and $479,557 in non-federal funding.

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