2011 — 2013 |
Barber, Annika Fitzpatrick |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Molecular Interactions of General Anesthetics in Voltage-Gated Sodium Channels @ Thomas Jefferson University
Despite the ubiquitous use of general anesthetics, the molecular basis of general anesthesia has yet to be elucidated. The long-term goal of this study is to shed light on the molecular basis of general anesthetic action, which may open novel opportunities to design safer general anesthetics. General anesthetics are thought to act on the central nervous system by directly interacting with membrane proteins. Since ion channels are the essence of electrical excitability in the nervous system, they are considered particularly relevant targets of general anesthetics. The central hypothesis of this proposal is that inhaled general anesthetics interact with discrete hydrophobic cavities and exert their physiological effects through allosteric coupling with an effector site involving the gating machinery of voltage-gated ion channels. This proposal investigates NaChBac, a bacterial homolog of mammalian voltage-gated sodium (Nav) channels, to characterize inhaled anesthetic interactions with voltage gated sodium channels. The aims of this project are 1) to investigate the contributions of the S4-S5 linker and the S6 segment to inhaled anesthetic action in a voltage-gated sodium, channel, and 2) to investigate the structural basis of inhaled anesthetic action in a voltage-gated sodium channel. To pursue these aims a combination of mutagenesis, patch-clamp electrophysiology, protein biochemistry, anesthetic photolabeling and molecular dynamics simulations will be used. This work will provide a stepping-stone to similar investigations of mammalian Nav channels, which are also modulated by relevant doses of inhaled anesthetics and open the door to mechanistic studies of anesthetic effects on Nav channels.
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2015 — 2016 |
Barber, Annika Fitzpatrick |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Integration of Sleep-Regulating Signals by the Drosophila Pars Intercerebralis @ University of Pennsylvania
? DESCRIPTION (provided by applicant): Although sleep is a fundamental process involved in survival and proper brain performance, how the brain determines when to fall asleep and wake up is still not understood. The importance of sleep is further underscored by accumulating evidence that sleep deprivation and circadian rhythm disruption contributes to chronic health issues, due to the role of sleep in many physiological processes including metabolism, immune function, memory consolidation and more. Sleep results from the sum of information from two systems: the circadian clock and the sleep homeostatic system. The circadian system contains a core molecular clock that is synchronized to the time of day by visual inputs and drives a 24h rhythm in many physiological processes and behaviors, including sleep. The sleep homeostasis system signals the need to sleep after prolonged wakefulness. How and where homeostatic and circadian information are integrated to drive sleep is not known. The central hypothesis of this proposal is that the Pars Intercerebralis (PI), an analog of the mammalian hypothalamus, receives and integrates both circadian and homeostatic information. The PI is involved in controlling both amount of sleep, which is a measure of the homeostatic system, as well as circadian timing of sleep. The PI is part of a circadian output pathway controlling rest-activity rhythms and likely receives input from multiple areas, including the core circadian clock and regions involved in sleep homeostasis. PI output is largely in the form of peptides released from distinct PI cell populations. These peptide signals may have diverse targets inside and outside the nervous system. The aims of this project are 1) To determine whether the firing of PI cells reflects circadian control; 2) To determine whether the firing behavior of PI cells is also affecte by the sleep homeostat and 3) To map the putative interactions of circadian and homeostatically controlled PI cells. To pursue these aims, a combination of Drosophila genetics and behavior, electrophysiology and calcium imaging will be used. Understanding the neural circuits involved in making sleep-wake decisions will open the door to novel hypotheses of how to influence these decisions to aid in healthy sleep and disease prevention.
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2018 — 2021 |
Barber, Annika Fitzpatrick |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Integration of Circadian and Homeostatic Signals in a Peptidergic Circuit in Drosophila @ University of Pennsylvania
There is rapidly accumulating evidence that disruptions of circadian patterns of sleep, activity and feeding lead to deleterious health consequences. While circadian clock mechanisms are well-studied, the relationship between time-of-day cues and homeostatic drives such as hunger are poorly understood. The integration of circadian information with nutritional cues occurs downstream of the core clock cells in the brain at the intersection of multiple behavioral circuits. This proposal exploits the Drosophila melanogaster genetic model to examine the mechanism by which circadian signals integrate with feeding circuitry to coordinate locomotor rhythms with feeding behavior. The Drosophila pars intercerebralis (PI), an analog of the mammalian hypothalamus, is a peptidergic center that receives both time-of-day and nutritional state information. Based on published and preliminary findings, I propose that the PI receives excitatory input from core clock neurons via neuropeptide signals, as well as inhibitory inputs from cholinergic Hugin-producing gustatory interneurons. I hypothesize that each of the peptidergic PI populations (DH44+, insulin-like peptide producing, SIFamide+ and Taotie) receives a unique set of inputs, which must then be integrated within the PI to coordinate behavioral outputs, and that this integration occurs via intra-PI paracrine neuropeptide signaling. Thus, PI populations likely modulate both rest:activity rhythms and feeding behavior depending on nutritional state to allow responses to acute environmental cues. In the mentored phase of this project I will characterize the connectivity from the central brain clock (Aim 1) and the hugin+ gustatory interneurons (Aim 2) to the PI and examine how each of these circuits modulates feeding and rest:activity behavior (Aims 1 and 2). In the independent phase of this project I will use skills gained in the mentored phase to investigate how starvation overrides clock control of PI neuron physiology and behavior (Aim 3) and the role of intra-PI connectivity in coordinating locomotor rhythms and feeding behavior (Aim 4). To pursue these aims I will use a combination of genetic tools including RNAi and CRISPR, physiological assays including electrophysiology and calcium imaging, and behavioral assays for locomotor rhythms and feeding. Successful completion of this project will offer important advances at both the level of neural circuitry and behavior. First, it will begin to elucidate how intersecting circuits communicate using neuromodulatory peptides. Neuromodulatory signaling has proven difficult to study in mammalian systems, and this work can offer insights that will be applicable to studies of neuropeptidergic regions in mammals, particularly in the hypothalamus. Second, it will advance understanding of the complex interplay of circadian rhythms and feeding both at the circuit and behavioral levels. Understanding not only how circuitry shapes behavior, but how behavior such as altered feeding patterns feeds back to the brain is important for developing interventions to improve human health.
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