The long-term goal of this multicenter PPG is to define the mechanisms responsible for the malignant hyperthermia syndrome caused by mutations in RyR1 and Cav1.1 as well as leveraging new discovery of other gene linkage in humans. The scope of investigations will range from extensive phenotyping of MH mice, studies of Ca2+ and Na+ homeostasis in muscle from MH mice and MHS humans and the importance of TRPCs (Project 1), studies of RyRI function, how MHS mutations cause posttranslational modifications, mitochondrial adaptations and metabolic abnormalities (Project 2), and how disruption of the normal interactions between RyR1 and CaVI.1 lead to Ca2+ dysregulation in MH susceptible animals and patients (Project 3), and the influence of MH mutations on the cellular physiology of muscle (Projects 1, 2, &3). Our research in the previous funding period has led to a unified general hypothesis applicable to any and all MH mutations: MH is caused by primary structural changes in RyRI, or by structural changes in RyRI induced indirectly by a mutation in Cavl.1 or another protein closely associated with RyR1 (as demonstrated by an MH like phenotype in Casq1 null mice). A transformative concept to be investigated by all PPG participants is that a defect in Cav1.1 f-RyR1 bidirectional signaling is a common convergent pathway leading to all MH susceptibility and progressive muscle damage. The focus of this program is tightly linked. All 3 Projects will: 1. Examine the relationship between gender and MH penetrance, 2. Validate the pathology in mouse models in human muscle. 3. Determine if the sequelae of MHS mutations can be reduced or prevented by genetic/pharmacological manipulations that decrease sarcolemmal Ca2+ entry, reduce RyR1 leak, increase SR Ca2+ load or scavenge lipid peroxides resulting from ROS production. 4. Using discovery from Core C establish the mechanisms by which newly discovered mutations not in RyR1 or Cav1.1 disrupt the normal bidirectional signaling between RyR1 and the DHPR leading to a common cascade causing MHS and its associated pathology, each using their unique expertise. In this way we assure that the outcome will be that the whole of this Program is greater than the sum of the individual parts.

Public Health Relevance

This multi-center interdisciplinary Program Project use the expertise of the three Project Principal Investigators supported by four Cores to uncover the molecular mechanisms that are the basis for Malignant Hyperthermia and Central Core Disease. This group of investigators have already shown the importance of how muscle proteins that cause contraction interact with each other and will discover how mutations that cause Malignant Hyperthermia disrupt of these interactions. In a broader sense these changes may well be applicable to all myopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR052354-07
Application #
8478052
Study Section
Special Emphasis Panel (ZAR1-MLB (M1))
Program Officer
Boyce, Amanda T
Project Start
2005-01-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$1,256,111
Indirect Cost
$263,325
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Franzini-Armstrong, Clara (2016) Can the Arrangement of RyR2 in Cardiac Muscle Be Predicted? Biophys J 110:2563-5
Polster, Alexander; Nelson, Benjamin R; Olson, Eric N et al. (2016) Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113:10986-91
Bannister, Roger A; Sheridan, David C; Beam, Kurt G (2016) Distinct Components of Retrograde Ca(V)1.1-RyR1 Coupling Revealed by a Lethal Mutation in RyR1. Biophys J 110:912-21
Ronjat, Michel; Feng, Wei; Dardevet, Lucie et al. (2016) In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide. Proc Natl Acad Sci U S A 113:E2460-8
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Franzini-Armstrong, Clara (2015) Electron Microscopy: From 2D to 3D Images with Special Reference to Muscle. Eur J Transl Myol 25:4836
Perni, Stefano; Marsden, Kurt C; Escobar, Matias et al. (2015) Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. J Gen Physiol 145:253
Henríquez-Olguín, Carlos; Altamirano, Francisco; Valladares, Denisse et al. (2015) Altered ROS production, NF-κB activation and interleukin-6 gene expression induced by electrical stimulation in dystrophic mdx skeletal muscle cells. Biochim Biophys Acta 1852:1410-9
Fiszer, Dorota; Shaw, Marie-Anne; Fisher, Nickla A et al. (2015) Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology 122:1033-46
Perni, Stefano; Marsden, Kurt C; Escobar, Matias et al. (2015) Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. J Gen Physiol 145:173-84

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