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High-probability grants
According to our matching algorithm, Johanna C. Gandy is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2010 — 2011 |
Gandy, Johanna C |
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.). |
Brain Mitochondria and Glycogen Synthase Kinase-3beta @ University of Alabama At Birmingham
DESCRIPTION (provided by applicant): NADH:ubiquinone oxidoreductase (complex-I) is the most common site of impairment of the oxidative phosphorylation-related disorders. These disorders include some neurodevelopmental and neurodegenerative syndromes such as Leigh syndrome, MELAS, and some forms of Parkinson's disease. While the clinical symptoms of complex-I deficiency are defined, signaling pathways regulating complex-I function in the mitochondria are less understood. Recently, our group found that unregulated glycogen synthase kinase-3[unreadable] (GSK3[unreadable]) activity inhibits complex-I function, increases reactive oxygen species production, fragments mitochondria, and increases the cell's sensitivity to complex-I toxins. GSK3[unreadable] is a signaling protein that is known to affect metabolic pathways and brain development. Its regulation is multi-tiered meaning that its actions can be controlled by phosphorylation at its serine-9 site, by protein-protein interactions, and by its intracellular localization. Interestingly, no one has fully elucidated its intracellular distribution in the brain. In preliminary results, we have found that a salient fraction of GSK3[unreadable] exists in brain mitochondria. Furthermore, we have now found previously undiscovered pockets of GSK3[unreadable] expression in other cellular compartments. The first specific aim of this proposal is to fully determine the neuroanatomic ultrastructural distribution of GSK3[unreadable] in the mouse and human brain by electron microscopy. A thorough investigation of this sort has not been conducted previously. The actions of endogenous GSK3[unreadable] signaling in the mitochondria are not fully known. In specific aim 2, the goal is to test the hypothesis that endogenous GSK3[unreadable] modulates complex-I functions. Endogenous mitochondrial GSK3[unreadable] activity is manipulated by molecular and pharmacological methods to assess the affects of GSK3[unreadable] signaling on complex-I. The proteins STAT3 and GRIM19 are bound together in the mitochondria and both are involved in complex-I function. It is also known that GSK3[unreadable] associates with both these proteins. Our hypothesis is that GSK3[unreadable] signaling regulates complex-I activity through a tripartite protein composite consisting of GSK3[unreadable], STAT3, and GRIM19. With this project we hope to elucidate mitochondrial GSK3[unreadable] signaling and its affects on complex-I with the prospect that our findings could be used to discover measures to alleviate complex-I disorders. PUBLIC HEALTH RELEVANCE: This project investigates the intracellular localization and functions of mitochondrial GSK3[unreadable], a protein whose unregulated activity has been previously implicated in severe mitochondrial deficiencies. In humans, mitochondrial dysfunctions have major ramifications on neurodevelopment and neurodegenerative diseases in both infants and adults.
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1 |
2013 |
Gandy, Johanna C |
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. |
Modulation of Camkii and Endocannabinoid Signaling by Calcium Channels
DESCRIPTION (provided by applicant): Normal habit learning, motor control, and decision making requires striatal GABA-ergic medium spiny neurons to integrate excitatory inputs with modulatory inputs from other basal ganglia structures. One major mechanism playing a key role in these processes is endocannabinoid (eCB) dependent plasticity. The major striatal eCB, 2-arachidonylglycerol (2-AG), is synthesized postsynaptically by diacylglycerol lipase-a (DGL) in response to synaptic activity, but acts retrogradely to inhibit presynaptic glutamate release and induce synaptic depression. Striatal L-Type voltage gated calcium channels (LTCCs) mediate calcium influx and are thought to drive synthesis of 2-AG to promote eCB-dependent synaptic depression. Another regulator of striatal calcium levels are T-type voltage gated calcium channels (TTCCs), which can make substantial contributions to calcium entry and have also been linked to eCB plasticity. However, few studies have directly measured changes in 2-AG levels following modulation of voltage gated calcium channel activity, nor have the calcium signaling pathways coupling LTCCs and TTCCs to striatal eCB plasticity been well characterized. Our lab has recently made the exciting discovery that Ca2+/calmodulin-dependent protein kinase-IIa (CaMKII) restrains DGL activity and 2-AG production to limit eCB-dependent synaptic depression (Nat Neurosci, 2013; 16(4):456- 63). Furthermore, work from our lab and others shows that CaMKII associates with and propagates signaling from LTCCs and TTCCs. My preliminary studies found that high striatal CaMKII activity and localization to the postsynaptic density under basal conditions requires ongoing entry of extracellular calcium entry, partially mediated by TTCCs. The goal of the proposed 1 year project is to test the overarching hypothesis that LTCCs and TTCCs differentially activate CaMKII to regulate eCB-dependent synaptic signaling with two specific aims: 1. Test the hypothesis that striatal CaMKII is differentially coupled to TTCCs and LTCCs. Acutely isolated striatal slices will be incubated with agonists and antagonists of these channels. Extracts and subcellular fractions will be analyzed by western blotting using phospho-site specific antibodies to monitor the CaMKII activation by autophosphorylation at Thr286 and by phosphorylation of established synaptic substrates (Ser831 in GluR1; Ser1303 in NR2B), and by immunohistochemical analyses of Thr286 autophosphorylation. 2. Test the hypothesis that LTCCs and TTCCs differentially modulate striatal DGL and 2-AG levels. I will assay DGL activity and 2-AG levels in extracts of striatal slices incubated under conditions similar to those defined in Aim 1 using a liquid chromatography/mass spectrometry based method. In combination, these studies will be the first to directly investigate how the modulation of striatal CaMKII Thr286 autophosphorylation by LTCCs and TTCCs regulates synaptic signaling and 2-AG synthesis. This will provide a firm foundation for future studies of potential disruptions of these pathways in striatal-based neurological and psychiatric diseases.
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0.948 |