Molecular Basis of Automaticity in the Myometrium

子宫肌层自动性的分子基础

基本信息

批准号：
7314146
负责人：
GLENNA C L BETT
金额：
$ 7.93万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7314146
关键词：
Accounting Age Behavior Behavioral Biochemical Genetics Biochemical Pathway Biochemistry Birth Blindness Cations Cells Cerebral Palsy Characteristics Class Communication Complex Condition Coupling Cyclic Nucleotides Data Defect Development Electrophysiology (science)Emotional Ethnic Origin Etiology Event Financial cost Fire - disasters Frequencies Gestational Age HCN1 channel Health Health Care Costs Hormonal Hospitalization Income Infection Ion Channel Length Life Lung diseases Measures Mediating Medical Membrane Membrane Potentials Mental Retardation Messenger RNA Modeling Molecular Molecular Biology Morbidity - disease rate Mus Muscle Muscle Contraction Myometrial Neonatal Neurodevelopmental Disability Pacemakers Patient currently pregnant Perinatal Care Physiological Pilot Projects Play Polymerase Chain Reaction Pregnancy Pregnant Uterus Premature Birth Premature Infant Premature Labor Process Property Protein Isoforms Recording of previous events Regulation Relative (related person)Resistance Rest Risk Risk Factors Role Second Messenger Systems Signal Transduction Speed Testing Therapeutic Intervention Time Tissues Transcript Up-Regulation Uterine Contraction Uterus Week base cost deafness density infancy mRNA Expression mortality myometrium neonatal morbidity novel prevent response second messenger social therapeutic target therapy design

项目摘要

DESCRIPTION (provided by applicant): Preterm birth (PTB), prior to the 37th week of gestation, significantly increases the risk of long-term complications such as neurodevelopmental disabilities, mental retardation, cerebral palsy, blindness, deafness and respiratory diseases, as well as communication and behavioral difficulties. Although some risk factors are known, 30-50% of spontaneous PTBs have an unknown etiology. Uterine contraction, like all smooth muscle contraction, is primarily an electromechanical event, i.e., an electrical signal initiates contraction. Although hormonal and biochemical pathways play key roles in developing parturition conditions, the speed and co-ordination of uterine excitation-contraction coupling indicates that the short-term coordinating signals for excitation in labor are carried by ion channels. The alteration of the electrical behavior of the myometrium during gestation must arise from changes in the expression level or behavior of the contributing ion channels. Spontaneous PTB therefore reflects abnormal timing in the development of the electrical activity of the uterus. Contraction during parturition results from rhythmic electrical activity (pacemaking) intrinsic to myometrium. One of the fundamental components of excitation-contraction coupling is the initiating depolarization, i.e., the "pacemaker" current. This proposal is based on my findings of a potential molecular basis for a uterine pacemaker current. My preliminary data show a unique class of ion channels, Hyperpolarization-activated Cyclic Nucleotide-sensitive (HCN) Cation Non-selective channels, in the uterus. In other tissues, these channels set the resting potential and generate rhythmic firing activity, i.e., are involved in pacemaking and automaticity. My preliminary data show that HCN1 mRNA expression is upregulated ~150 fold and HCN4 transcript is downregulated ~50 fold in late gestation relative to non-pregnant myometrium. HCN1 channels activate ~10 fold faster and are activated at a potential ~ 30 mV more depolarized than HCN4 channels, suggesting a major increase in HCN-mediated spontaneous electrical activity in late gestation. This dramatic pregnancy related upregulation of the HCN channel isoform which is most easily and rapidly activated (HCN1), is hypothesized to result in increased spontaneous myometrial excitation and consequently contraction. My hypothesis is that the upregulation of HCN1 mRNA contributes to pacemaking in the pregnant uterus. The aim of this proposal is to molecularly identify HCN channel isoforms in the myometrium and to electrophysiologically identify and characterize the corresponding cellular currents. Preterm birth results in enormous medical, social, emotional and financial costs. Currently, there are no effective ways to prevent preterm birth. Identification of an ion channel which is the uterine pacemaker offers the opportunity for designing interventions to prevent and delay preterm labor. Preterm birth results in enormous medical, social, emotional and financial costs. Currently, there are no effective ways to prevent preterm birth. Identification of an ion channel which is the uterine pacemaker offers the opportunity for designing interventions to prevent and delay preterm labor.

描述（由申请人提供）：早产（PTB），在孕期第37周之前，大大增加了长期并发症的风险，例如神经发育障碍，智力低下，脑麻痹，失明，聋哑和呼吸系统疾病，以及沟通和行为困难。尽管已知一些危险因素，但30-50％的自发PTB具有未知的病因。与所有平滑肌收缩一样，子宫收缩主要是机电事件，即电信号启动收缩。尽管荷尔蒙和生化途径在发展分娩条件中起着关键作用，但子宫激发触发偶联的速度和协调性表明，劳动激发的短期协调信号由离子通道携带。妊娠期间肌层的电行为的改变必须是由于促进离子通道的表达水平或行为的变化而产生的。因此，自发的PTB反映了子宫电活动发展中异常的时机。分娩过程中的收缩是由节奏电活动（起搏）固有的。激发反应耦合的基本组成部分之一是启动去极化，即“起搏器”电流。该提案基于我对子宫起搏器电流的潜在分子基础的发现。我的初步数据显示了子宫中独特的离子通道，超极化激活的循环核苷酸敏感（HCN）阳离子非选择性通道。在其他组织中，这些通道设定了静息电位并产生节奏的发射活动，即参与起搏和自动化。我的初步数据表明，HCN1 mRNA表达被上调〜150倍，而HCN4转录本在妊娠晚期相对于非妊娠子宫骨肌的后期下调了〜50倍。 HCN1通道激活〜10倍，并以比HCN4通道更具去极化的约30 mV激活，这表明在妊娠后期，HCN介导的自发性电活动的大幅增加。最容易和迅速激活的HCN通道同工型的这种戏剧性妊娠上的上调（HCN1）被认为会导致自发性肌层激发增加，从而导致收缩。我的假设是，HCN1 mRNA的上调有助于孕妇子宫的起搏。该建议的目的是分子鉴定肌层中的HCN通道同工型，并在电生理上识别和表征相应的细胞电流。早产会导致巨大的医疗，社会，情感和财务成本。目前，没有有效的方法来防止早产。识别子宫起搏器的离子通道为设计干预措施预防和延迟早产提供了机会。早产会导致巨大的医疗，社会，情感和财务成本。目前，没有有效的方法来防止早产。识别子宫起搏器的离子通道为设计干预措施预防和延迟早产提供了机会。