Functional Analysis of Carotid Body Responses to Hypoxia in Mice"

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DESCRIPTION (provided by applicant): The carotid body's role in sensing hypoxia is well established. It has also been implicated in several human health disorders such as SIDS, Sleep Apnea, Congenital Central Hypoventilation Syndrome, chronic heart failure and primary hypertension. Furthermore, these disorders have been strongly linked to a genetic predisposition. In order to study genetically linked disorders, an inbred or genetically manipulated mouse model is an ideal tool for investigation. In response to hypoxia, the carotid body activates respiratory centers via increasing the carotid chemoreceptor afferent nerve output. Thus, the most direct method for studying the overall carotid body's function is measuring the afferent carotid sinus nerve activity. Such studies have been done mostly in large animals. Although several studies have recorded mouse carotid sinus nerve activity in vitro, its characteristics are still not well described. Needless to say, studies in vivo using inbred or genetically manipulated mice are required in order to directly link genetics with altered carotid body function and human health disorders. The long term objective of my research is to study the role that genetics play in modulating carotid body function and carotid body-related human health disorders. For this application, I shall bridge in vivo assessment of the carotid body function and one molecular target, BK channels. BK channels are present in chemosensing glomus cells of the carotid body and are inhibited by hypoxia. Downstream from this oxygen sensing element is an increase in intracellular calcium in glomus cells followed by neurotransmitter release and a subsequent change in carotid sinus nerve activity. AIM 1 is to develop an in vivo murine model to study CB responses to hypoxia. I will establish in vivo CSN recordings in C57BL/6J mouse strain that is the background strain in many genetically altered mice. In aim 2,1 will explore the role that BK channels play in the overall in vivo carotid body responses to hypoxia. I will use the DBA/2J strain with its higher expression of functional BK channels, the A/J strain with lower expression of BK channels, and BK channel knockout mice (BK-KO) to study the role that BK channels play within the carotid body in response to hypoxia. These two aims will allow us to characterize the role that BK channels play within a functional scope. In order to link this work to chemoreceptor cell function, I will try to link AIM 2's in vivo responses to in vitro measures of glomus cell function. One of the main-stream methods of studying carotid body function in vitro is by measuring changes in glomus cell intracellular calcium. Accordingly, the last aim of my research will be to explore the association between BK channels composition, CSN activity and changes in glomus cell intracellular calcium in the mouse carotid body (AIM 3).