This proposal is a direct extension of my original study to determine the role of catecholamines in embryogenesis. This work was initiated by the finding that catecholamine-deficient mice die at midgestation. My focus is now directed at identifying which adrenergic receptor (AR) mediates these catecholaminergic effects. This question is particularly salient given the discovery that knockout mice lacking all three cloned beta- ARs are completely viable. Data gathered over the past 18 months suggest that catecholamines act at a """"""""beta-like"""""""" AR to mediate survival and regulate fetal heart rate during periods of hypoxic stress. The exact identity of this receptor, however, is still unknown. My findings suggest that this receptor may be a new, as yet unidentified, beta-AR, which would correlate with the viability of the beta-AR knockout mice.
Specific Aim 1 : Determine the pharmacological profile of the physiologically relevant receptor by monitoring heart rate in response to various AR antagonists.
Specific Aim 2 : Determine why triple beta-AR mice are viable: Do they no longer require catecholamines? Do they use an alpha-AR instead of a beta-AR? Do they use a novel beta-AR and, if so, what is the pharmacology of this receptor? In order to test this, quadruple knockout mice will be made by breeding the TH mutation onto the triple beta-AR knockout mice. If the triple beta-AR knockout mice rely on catecholamines then the addition of the TH mutation should result in embryo death. This work has direct clinical significance. If our hypothesis that catecholamines maintains cardiac function in response to hypoxic stress in utero is true in humans, the current practice of prescribing beta-blockers for the treatment of pregnancy-induced hypertension could exacerbate transient fetal ischemia and, in extreme cases, be life-threatening. If a novel beta-AR mediates the fetal """"""""survival response"""""""", drugs could be developed to target maternal receptors while leaving fetal beta-ARs unaffected.
| Chandra, Rashmi; Portbury, Andrea L; Ray, Alisa et al. (2006) Beta1-adrenergic receptors maintain fetal heart rate and survival. Biol Neonate 89:147-58 |
| Portbury, Andrea L; Chandra, Rashmi; Groelle, Marybeth et al. (2003) Catecholamines act via a beta-adrenergic receptor to maintain fetal heart rate and survival. Am J Physiol Heart Circ Physiol 284:H2069-77 |
