Research Awards
Jan Marino Ramirez, Ph.D.
University of Chicago
"Neural Mechanisms Underlying Erratic Breathing"
2-Year Award: $78,960
Lay Progress Report:
Increasing evidence indicates that Rett Syndrome children are deficient in Substance P (SP) in brainstem areas that are associated with the central control of breathing. We use an animal model to investigate the consequences of Substance P deficiency and the role of substance P in controlling the regularity of breathing.
In the first funding period we concentrated on investigating two issues: (1) how does substance P regulate the frequency and regularity of respiratory network activity and (2) which intracellular, second messenger pathways mediate the substance P effect. Understanding both, the network and intracellular mechanisms, is important for the future development of a rationale therapy for erratic breathing. Our investigations yielded two unexpected results: (1) The regularity and the frequency of respiration depends on synaptic interactions between neurons with pacemaker and non-pacemaker properties. This interaction is controlled by both NMDA and GABAergic synaptic mechanisms. Enhancing NMDA and GABAergic synaptic mechanisms suppresses pacemaker properties and enhances the synchronization between non-pacemaker respiratory neurons, which then results in an increased regularity of breathing and decreased frequency of breathing. We currently investigate the hypothesis that deficiency in substance P leads to a decreased activation of NMDA and GABAergic mechanisms, which then result in erratic breathing. (2) A second set of experiments examined which second messenger pathways are involved in the substance P modulation of breathing.
We can demonstrate that the phospholipase D pathway is involved in the SP effect on sigh activity. However, despite examining all major second messenger pathways, we were unable to identify a second messenger system that mediates the SP effect on eupneic (normal, regular breathing) activity. Therefore, we currently test the hypothesis that the SP effect on eupneic activity is mediated by a membrane-delimited G-protein modulation and not by a cytoplasmic second messenger system.
We predict that understanding how substance P deficiency within the CNS leads to an irregularity of breathing is an important first step to treat erratic breathing. In the second funding period we will continue to unravel the underlying cellular mechanisms.
Jan Marino Ramirez, Ph.D.University of Chicago
"Neural Mechanisms Underlying Erratic Breathing"
2-Year Award: $78,960
Lay Progress Report:
Increasing evidence indicates that Rett Syndrome children are deficient in Substance P (SP) in brainstem areas that are associated with the central control of breathing. We use an animal model to investigate the consequences of Substance P deficiency and the role of substance P in controlling the regularity of breathing.
In the first funding period we concentrated on investigating two issues: (1) how does substance P regulate the frequency and regularity of respiratory network activity and (2) which intracellular, second messenger pathways mediate the substance P effect. Understanding both, the network and intracellular mechanisms, is important for the future development of a rationale therapy for erratic breathing. Our investigations yielded two unexpected results: (1) The regularity and the frequency of respiration depends on synaptic interactions between neurons with pacemaker and non-pacemaker properties. This interaction is controlled by both NMDA and GABAergic synaptic mechanisms. Enhancing NMDA and GABAergic synaptic mechanisms suppresses pacemaker properties and enhances the synchronization between non-pacemaker respiratory neurons, which then results in an increased regularity of breathing and decreased frequency of breathing. We currently investigate the hypothesis that deficiency in substance P leads to a decreased activation of NMDA and GABAergic mechanisms, which then result in erratic breathing. (2) A second set of experiments examined which second messenger pathways are involved in the substance P modulation of breathing.
We can demonstrate that the phospholipase D pathway is involved in the SP effect on sigh activity. However, despite examining all major second messenger pathways, we were unable to identify a second messenger system that mediates the SP effect on eupneic (normal, regular breathing) activity. Therefore, we currently test the hypothesis that the SP effect on eupneic activity is mediated by a membrane-delimited G-protein modulation and not by a cytoplasmic second messenger system.
We predict that understanding how substance P deficiency within the CNS leads to an irregularity of breathing is an important first step to treat erratic breathing. In the second funding period we will continue to unravel the underlying cellular mechanisms.