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. ? ? ? ?
| Bett, Glenna (2012) Quantitative Analysis of Uterine Action Potentials. J Genit Syst Disord 1:1000e102 |
| Bader, Patrick L; Faizi, Mehrdad; Kim, Leo H et al. (2011) Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A 108:15432-7 |
