Differences between MH/CCD and wild type (Wt) genotypes

$273,393P01FY2008ARNIH

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

The long-term objective in Project 2 is to gain understanding of the biochemical and biophysical[unreadable] mechanisms by which mutations from each MH/CCD hot spot alter key regulatory functions of the[unreadable] RyR1 Ca2+ channel complex, and how these changes deregulate SR Ca2+ transport in skeletal[unreadable] muscle SR, and dendritic cells that express MH/CCD RyR1.[unreadable] HYPOTHESIS I) MH/CCD mutations alter cytoplasmic and luminal regulation of RyR1 by ligands[unreadable] by changing the activation energy (Ea) needed for conformational transitions of the channel.[unreadable] A1.1. Define differences among 11 MH/CCD and wild type (Wt) genotypes on expression of key[unreadable] triadic proteins, SR loading capacity and their relationship to altered cation interactions at H- and Lsites[unreadable] using equilibrium [3H]ryanodine ([3H]Ry) binding analysis. A1.2. To analyze mechanisms[unreadable] responsible for altered regulation by cytoplasmic Ca2+, Mg2+, and ATP and luminal Ca2+ anc[unreadable] calsequestrin (CSQ) using selected RyR1 channels. A1.3. Compare the differences in activation[unreadable] energy (Ea) for selected MH/CCD mutations. A1.4. Analyze how halothane and dantrolene[unreadable] differentially influence the stability of closed and open states of selected MH/CCD RyR1s.[unreadable] HYPOTHESIS II) MH/CCD mutations disrupt the redox-sensing properties of RyR1.[unreadable] A2.1. To establish if differences in transmembrane redox regulation and GSH/GSSG transport[unreadable] contribute to the pathophysiology of MH/CCD.[unreadable] HYPOTHESIS III) MH/CCD mutations produce a dysfunctional phenotype in dendritic cells.[unreadable] A3.1. Elucidate how MH/CCD mutations alter murine dendritic cell activation, dendritic cell secretion[unreadable] of IL-6 mediated by ATP acting at P2Y receptors, and if and how MH/CCD mutations influence[unreadable] dendritic cell activation of T-cells. A3.2. To extend these studies to DCs cultured from human blood.

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