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.
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.
|Riazi, Sheila; Kraeva, Natalia; Hopkins, Philip M (2018) Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept. Anesthesiology 128:168-180|
|Zheng, Jing; Chen, Juan; Zou, Xiaohan et al. (2018) Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration. Neurotoxicology 70:112-121|
|Lavorato, Manuela; Loro, Emanuele; Debattisti, Valentina et al. (2018) Elongated mitochondrial constrictions and fission in muscle fatigue. J Cell Sci 131:|
|Glaser, Nosta; Iyer, Ramesh; Gilly, William et al. (2018) Functionally Driven Modulation of Sarcomeric Structure and Membrane Systems in the Fast Muscles of a Copepod (Gaussia princeps). Anat Rec (Hoboken) 301:2164-2176|
|Polster, Alexander; Nelson, Benjamin R; Papadopoulos, Symeon et al. (2018) Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1. J Gen Physiol 150:613-624|
|Holland, Erika B; Goldstone, Jared V; Pessah, Isaac N et al. (2017) Ryanodine receptor and FK506 binding protein 1 in the Atlantic killifish (Fundulus heteroclitus): A phylogenetic and population-based comparison. Aquat Toxicol 192:105-115|
|Perni, Stefano; Lavorato, Manuela; Beam, Kurt G (2017) De novo reconstitution reveals the proteins required for skeletal muscle voltage-induced Ca2+ release. Proc Natl Acad Sci U S A 114:13822-13827|
|Lavorato, Manuela; Iyer, V Ramesh; Dewight, Williams et al. (2017) Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. Proc Natl Acad Sci U S A 114:E849-E858|
|Zhang, Rui; Pessah, Isaac N (2017) Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A. Mol Pharmacol 91:428-436|
|Linsley, Jeremy W; Hsu, I-Uen; Groom, Linda et al. (2017) Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proc Natl Acad Sci U S A 114:E228-E236|
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