Environmental and Epigenetic Modifiers of Susceptibility to Malignant Hyperthermia and Environmental Heat Stroke

恶性高热和环境中暑易感性的环境和表观遗传因素

• 批准号: 10606166
• 负责人: JAMES J DOWLING
• 金额: $ 79.69万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-28 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606166
• 关键词: 5' -AMP-activated protein kinase; Age; Body Temperature; Caffeine; Cause of Death; Cessation of life; Clinical; Complex; Coupling; DNA Methylation; Dantrolene; Data; Development; Disease; Dominant-Negative Mutation; Environment; Epigenetic Process; Event; Exercise; Exhibits; Exposure to; Family; Fatty-acid synthase; Feedback; Female; Fever; Frequencies; Genes; Genetic; Glycolysis; Goals; Heat Stress Disorders; Heat Stroke; Heritability; Heterozygote; Human; Incidence; Individual; Life Experience; Macromolecular Complexes; Malignant hyperpyrexia due to anesthesia; Measures; Mediating; Metabolic; Military Personnel; Modification; Molecular; Mus; Mutation; Operative Surgical Procedures; Outcome; Partner in relationship; Pathogenicity; Patients; Penetrance; Predisposition; Prevention; Production; Proteins; Reporting; Role; RyR1; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Serum; Severities; Sex Bias; Skeletal Muscle; Teenagers; Temperature; Testing; Thermogenesis; Variant; effective therapy; epigenome; inhibitor; intergenerational; male; metabolomics; mouse model; muscle form; novel strategies; offspring; pediatric patients; prevent; protein expression; response; sex; skeletal muscle metabolism; transgenerational epigenetic inheritance; transmission process; young adult

Mutations in the skeletal muscle (SkM) sarcoplasmic reticulum (SR) Ca2+ release channel (Ryanodine Receptor Type 1, RYR1), a component of the macromolecular complex that controls SkM excitation- contraction coupling (ECC), are known genetic causes of Malignant Hyperthermia sensitivity (MHS) and Environmental Heat Illness/Environmental Heat Stroke (EHI/EHS). MHS/EHS display incomplete penetrance, variable expressivity and discordant inheritance. The reasons for this variability remain enigmatic. There are no effective treatments for individuals with RYR1 pathogenic variants who experience life-threatening MHS/EHS episodes outside of clinical settings (febrile pediatric patients, athletes, military personnel in hot environments). Our goal is to develop approaches to prevent EHI-related deaths associated with RYR1 pathogenic variants. We propose the existence of an environmentally sensitive, epigenetically regulated, feedback loop between SkM and BAT that sensitizes MHS humans and mice to heat. Our specific hypotheses are: 1) Heat and increased SkM activity drive metabolic and epigenetic changes in SkM and BAT to increase thermogenesis in MHS mice. 2) Increased body temperature in MHS mice enhances SR Ca2+ leak, lactate production, AMPK activation and metabolic changes in SkM, which, in turn, drive epigenetic modifications in SkM and BAT that further enhance sensitivity to heat. 3) Heat-driven epigenetic changes are sex-biased and heritable and contribute to discordance These hypotheses will be tested in 3 Specific Aims. Specific Aim 1: Define the roles of heat, glycolysis, lactate, and adaptive thermogenesis in the enhanced sensitivity of MHS/EHS mice to heat. Specific Aim 2: Define the role of RyR1 Ca2+ leak and AMPK activation in SKM on the enhanced sensitivity of MHS mice to heat. Specific Aim 3: Determine if epigenetic changes driven by heat are heritable and sex biased. Completion of these studies will elucidate fundamental molecular and epigenetic mechanisms that underlie variability in EHS penetrance, expressivity, and genetic discordance, as well as provide new information on the complex interplay of environment and genetics in these disorders. These data will lead to a new understanding of the drivers of EHS episodes and, ultimately, to strategies for their prevention.

骨骼肌（SKM）肌质网（SR）CA2+释放通道（ryanodine受体）中的突变 1型，RYR1），大分子复合物的组成部分，该复合物控制SKM激发 - 收缩耦合 （ECC）是已知的恶性高温敏感性（MHS）和环境热的遗传原因 疾病/环境热中风（EHI/EHS）。 MHS/EHS显示出不完整的外观，可变表达性 和不一致的继承。这种可变性的原因仍然是神秘的。没有有效的治疗 对于有RYR1致病变体的人，他们经历了威胁生命的MHS/EHS情节 临床环境（火热的儿科患者，运动员，在热环境中的军事人员）。 我们的目标是开发方法，以防止与RYR1致病变异相关的EHI相关死亡。 我们提出存在环境敏感，表观遗传调节的反馈回路的存在 Skm和蝙蝠使MHS人类和小鼠加热。我们的具体假设是：1）热和 SKM活性的增加驱动SKM和BAT的代谢和表观遗传变化，以增加生热发生 MHS小鼠。 2）MHS小鼠的体温升高可增强SR Ca2+泄漏，乳酸产生，AMPK SKM的激活和代谢变化，这反过来驱动SKM和BAT中的表观遗传修饰 进一步增强对热的敏感性。 3）热驱动的表观遗传变化是性别偏见和可遗传的， 有助于不一致的这些假设将以3个特定目的进行测试。特定目标1：定义角色 MHS/EHS小鼠对热的敏感性增强的热量，糖酵解，乳酸和适应性热发生。 特定目标2：定义RYR1 Ca2+泄漏和AMPK激活在SKM中的作用在增强的灵敏度上 MHS小鼠加热。特定目的3：确定由热量驱动的表观遗传变化是否可遗传和性偏见。 这些研究的完成将阐明基本的基本分子和表观遗传机制 EHS外观，表现性和遗传不一致的变异性，并提供有关该信息的新信息 这些疾病中环境和遗传学的复杂相互作用。这些数据将导致新的理解 EHS情节的驱动因素，最终是预防策略。