Contributions of Astrocyte Kir4.1/5.1 Channels to Disordered Breathing in Rett Syndrome

星形胶质细胞 Kir4.1/5.1 通道对 Rett 综合征呼吸障碍的影响

• 批准号: 10606795
• 负责人: Monica Strain
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-06 至 2027-01-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606795
• 关键词: Affect; Animal Model; Animals; Astrocytes; Behavior; Brain; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cessation of life; Data; Disease; Electrophysiology (science); Failure; Future; Genes; Genotype; Goals; Homeostasis; In Vitro; Link; Mediating; Membrane Potentials; Methyl-CpG-Binding Protein 2; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Online Mendelian Inheritance In Man; Patients; Phenotype; Positioning Attribute; Process; Quality of life; Reflex action; Regulation; Research Personnel; Respiration Disorders; Rett Syndrome; Role; Science; Seizures; Site; Slice; Symptoms; Testing; Tissues; Training; Wakefulness; Whole Body Plethysmography; Work; autistic behaviour; comorbidity; extracellular; human model; insight; loss of function mutation; mortality; mouse model; premature; respiratory; response; targeted treatment; training opportunity

SUMMARY Rett syndrome (RTT) (OMIM #312750) is a severe X-linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2). Although RTT patients suffer from many co-morbid phenotypes, wake disordered breathing has a major negative impact quality of life and is associated with high mortality rate. Evidence from mouse models of RTT suggest disordered breathing results in part from a disrupted ability to regulate breathing in response to changes in tissue CO2/H+ (i.e., central chemoreflex). The retrotrapezoid nucleus (RTN) is an important site of chemoreception, neurons and astrocytes in this region sense changes in CO2/H+ to regulate breathing. Previous work identifies heteromeric Kir4.1/5.1 channels as key determinants of RTN astrocyte CO2/H+ chemosensitivity. However, homomeric Kir4.1 and heteromeric Kir4.1/5.1 are differentially CO2/H+ sensitive and regulate divergent astrocyte processes including membrane potential and clearance of neuronally released extracellular K+, and it is not clear which of these mechanisms contributes to RTN chemoreception and disordered breathing in RTT. Previous work from my sponsors group showed that MeCP2 deficient mice have reduced levels of both Kir4.1 and 5.1 channels, diminished astrocytic Kir4.1 mediated currents and dysregulated extracellular K+. Preliminary data also show that global deletion of Kir4.1 from astrocytes blunts the ventilatory response to CO2, while re-expression of Kir4.1 specifically in RTN astrocytes rescued this respiratory phenotype. Based on this, I hypothesize that MeCP2 deficiency results in loss of Kir4.1/5.1 and compromised astrocyte chemoreception that contributes to disordered breathing in RTT. To explore this possibility, I will test the following two Specific Aims: 1) Determine roles of astrocyte Kir4.1 containing channels in RTN chemoreception in vitro; and 2) Identify differential roles of Kir4.1 and Kir5.1 channels in the control of breathing in RTT. Understanding how Kir4.1 and Kir5.1 contribute to RTN chemoreception and disordered breathing may provide mechanistic insight for targeted treatment of disordered breathing in RTT. This work will also provide valuable training opportunities in molecular, cellular and whole- animal approaches that will prepare me for a successful future in science.

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