1981 — 1983 |
Huang, Hai |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Research Initiation: Two Noise Corrupted Recursive Algorithms and Their Applications in Stochastic Optimization |
0.961 |
2012 — 2016 |
Huang, Hai |
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. |
Ion Channels and Presynaptic Function of An Auditory Synapse @ Oregon Health & Science University
DESCRIPTION (provided by applicant): The reliability and precision of synaptic transmission are required by circuits of the auditory brainstem in order to encode timing with sub-millisecond accuracy. Synaptic transmission is refined by the complement of different ion channels at nerve terminals, which determines spike threshold and shape, and the ability to support high-frequency firing. The long-term goal of this research is to understand the synaptic mechanisms that contribute to these functions. Recently, an immunohistochemical study showed that an unusual K+ channel subtype, KCNQ5, is present at all excitatory terminals of the auditory brainstem. KCNQ (Kv7) channels are tightly associated with human neuronal and heart diseases. In the CNS, although the function of somatic KCNQ channels has been extensively examined in a variety of cell types, little attention has been paid to the synapse, in part because the small size of nerve terminals usually precludes their direct measurement. The calyx of Held, whose large size permits whole-cell patch-clamp recording, is an exceptional preparation that allows us direct analysis of presynaptic KCNQ channels. We found that the KCNQ5 channel is the major K+ channel responsible for setting the resting properties of the calyx. Modulation of the channel controls resting properties, subthreshold electrical activity, and transmitter release probability. Block of the channel also has profound effects on presynaptic excitability. In this application, we aim to determine how KCNQ channel controls the presynaptic excitability of auditory synapses. First, we will use a combination of immunohistochemistry, electrophysiology and 2-photon imaging to test the hypothesis that inhibition of KCNQ5 leads calyx of Held to altered spike firing as a result of inactivation of axonal and axon terminal ion channels (Kv1 and NaV). Results will be then incorporated into a complete model of propagation and excitation of presynaptic to account for the role of KCNQ. The modeling data will be confirmed by predicting the experimental results from partially blocking of key presynaptic channels. Since KCNQ5 is a component of all excitatory terminals in the lower auditory system, we will also examine the role of KCNQ at terminals in the cochlear nucleus whose function differs dramatically from the calyx. Preliminary data indicate that block of KCNQ channels suppresses exocytosis of granule cell parallel fiber into cartwheel cells, suggesting they may be required to maintain a full presynaptic spike waveform. We will examine the role of KCNQ in controlling transmitter release at terminals in the cochlear nucleus. The study of this proposal will extend our understanding of presynaptic KCNQ function, which may have implications for neurological disorders that are characterized by persistent activity, such as tinnitus or epilepsy. Thus, this application is important not only for basic science by enriching our knowledge of presynaptic ion channels and then physiological role KCNQ channel in the nervous system, but also for public health by providing possible insight into KCNQ-related diseases. PUBLIC HEALTH RELEVANCE: KCNQ channels play crucial roles in controlling neuron excitability and are implicated in human diseases, including deafness and epilepsy. Neuronal hyperexcitability and correlated plasticity changes may cause audiogenic seizure and tinnitus. The direct studying of the presynaptic KCNQ channels in this proposal, in combination of the somatic KCNQ function, will extend our knowledge of KCNQ function and obtain a more complete understanding of KCNQ-related disease and neurological disorders characterized by persistent activity.
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1 |
2018 — 2021 |
Huang, Hai |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synaptic Mechanisms of Auditory Information Processing @ Tulane University of Louisiana
PROJECT SUMMARY The reliability and precision of synaptic transmission are required in circuits of the auditory brainstem in order to encode timing with submillisecond accuracy. Auditory information is encoded by action potentials phase-locked to sound frequency at high rates. Accordingly, synaptic vesicles need to be recycled and refilled rapidly. Accumulating studies have uncovered the processes of vesicle fusion and recycling; however, the control of the contents of synaptic vesicles has received considerably less attention. Reasons for this gap in our understanding include the small size of synaptic vesicles and of conventional synapses, the complex ionic basis for loading of neurotransmitter into vesicles, and the difficulty in manipulating and assessing vesicle loading in physiological conditions. We have recently found that a Na+/H+ exchanger expressed on synaptic vesicles promotes vesicle filling with glutamate. Using the calyx of Held, a giant glutamatergic synapse in the auditory brainstem that permits direct pre- and postsynaptic recordings and manipulation of the presynaptic cytosol, we showed that glutamate loading is facilitated by intracellular Na+ over the physiological concentration range. Na+ influx through presynaptic plasma membrane HCN channels affects presynaptic Na+ concentration, regulates glutamate uptake, and thus controls miniature excitatory postsynaptic currents. Here we propose that during high-frequency signaling, when large amounts of glutamate are released, Na+ accumulates in terminals and facilitates glutamate uptake into synaptic vesicle, accelerating vesicle replenishment and sustaining reliable synaptic transmission. We further hypothesize that the control of vesicle loading, release and recycling can be affected by hearing loss. This work will establish a new fundamental role of Na+ to link activity and synaptic function under physiological and pathological conditions.
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1 |
2021 |
Huang, Hai |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preoperative Exercise Therapy For Surgery Triggered Inflammation
PROJECT SUMMARY Liver ischemia and reperfusion (I/R) is an unavoidable consequence of major liver resection and liver transplantation that leads to significant morbidity, mortality, and costs after liver surgery. However, previous strategies to protect the liver from I/R injury have focused on one specific known injury mechanisms, leaving intact other detrimental processes. Pre/post-operative exercise facilitates recovery after major abdominal surgery. It is known that exercise confers beneficial effects on the surgical outcome by regulating multiple mechanisms, including alteration of quantity and function of innate immune cells to provide an anti- inflammatory environment. Our novel preliminary data indicate that preoperative exercise therapy (PET) significantly reduced serum aminotransferase levels (liver damage) and expression of cytokines and chemokines (inflammatory responses) during liver I/R. Our single-cell RNA-sequencing (scRNA-seq) data revealed PET altered the transcriptomic profile of resident Kupffer cells (KCs) towards an anti-inflammatory profile. PET also promoted the anti-inflammatory trained immunity in Kupffer cells which is associated with increased circulating damage-associated molecular pattern (DAMP) IL-33 and itaconate metabolic reprogramming. Furthermore, we show that PET significantly decreased the number of neutrophils and formation of neutrophil extracellular traps (NETs), as key mediators of local and systemic injury after liver I/R. Given these findings, we hypothesize that PET prevents liver I/R injury by altering the trained immunity in Kupffer cells, and the NET-induced local and systemic inflammatory response. We will test our hypothesis by pursuing two specific aims. In Aim 1, we will determine the mechanism by which PET protects the liver from I/R injury via training Kupffer cells towards an anti-inflammatory phenotype. We will test the hypothesis that PET induces an anti-inflammatory trained immunity in KCs via modulation of IL-33/ST2/STAT3 signaling pathway and itaconate/IRG1 metabolic reprogramming pathway. In Aim 2, we will define the role of PET in attenuating local and systemic injury during liver I/R via reduction of neutrophil extracellular traps. We will test the hypothesis that PET ameliorates systemic inflammatory injury after liver I/R through suppression of neutrophil recruitment and formation of NETs. Our proposal will delineate the molecular mechanisms of PET in the regulation of hepatic immune microenvironment, and systemic immunity during liver I/R. The mechanisms discovered in these studies will provide the foundation for not only optimizing this non-pharmacological-based strategy against surgery-induced organ injury but also devising exercise-mimicking pharmacological strategies for patients undergoing surgery who are exercise intolerant.
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0.961 |