Michael S. Clark, MD, PhD - US grants
Affiliations: | Psychiatry and Behavioral Neuroscience | University of Washington, Seattle, Seattle, WA |
Area:
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Michael S. Clark is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
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| 1994 — 1997 | Clark, Michael S | F30Activity Code Description: Individual fellowships for predoctoral training which leads to the combined M.D./Ph.D. degrees. |
Regulation of Serotonin Synthesis in Neural-Like Cells @ University of Iowa |
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| 2002 — 2004 | Clark, Michael S | 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. |
Stress and 5-Ht1b Autoreceptors in Models of Anxiety @ University of Washington DESCRIPTION (provided by applicant): Serotonin (5-HT)1B autoreceptors are localized in the axon terminals of serotonergic neurons and provide feedback inhibition of serotonin synthesis and release. However, 5-HT1B receptors are expressed in many neuron types, making pharmacological analysis nearly unable to discern which populations produce a particular behavioral or physiological effect. This has led to confusion about their role in depressive and anxiety symptoms associated with impaired serotonergic neurotransmission. Most 5-HT fibers projecting to regions involved in these functions arise from the dorsal (DRN) or median (MRN) raphe nuclei, but there is considerable uncertainty as to how 5-HT release from these nuclei is controlled in disease states. We have been using viral gene transfer to examine the effects of DRN 5-HT1B over-expression on stress-sensitivity in two anxiety-related behaviors - open field test (OFT) and elevated-plus maze (EPM). In agreement with previous results showing increased DRN 5-HT1B expression in learned helpless rats, we found 5-HT1B overexpression in DRM increases anxiety behaviors. I propose to extend these studies to examine effects of 5-HT1B overexpression in the MRN, where I anticipate increased magnitude of EPM effects due to the involvement of MRN in benzodiazepine actions in this assay. To further establish the role of increased 5-HT1B autoreceptor expression in these effects, I will determine if SB-224289, a 5-HT1B antagonist reverses them. Finally. I will examine the effects of a key modulator of stress, corticotropin releasing factor (CRF), on 5-HT1B expression in the DRN. Since DRN and amygdala are reciprocally connected via 5-HT and CRF, investigating the functional relationship between CRF and 5-HT1B autoreceptors may help explain the interactions that these brain regions have in fear and anxiety behaviors. CRF has complex effects on 5-HT release from DRN projections, perhaps because both CRF receptors (R1 and R2) are expressed in DRN. CRF-R1 appears to inhibit 5-HT release, while CRF-R2 is excitatory. We propose to investigate the effect of subchronic infusion of selective CRF agonists into DRN on 5-HT1B mRNA regulation and anxiety behaviors. Chronic R1 activation should accordingly decrease 5-HT1B expression in DRN while increasing anxiety related behavior, while chronic R2 activation should produce the opposite effects. |
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| 2006 — 2010 | Clark, Michael S | K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
The Dorsal Raphe and Crf: Making the Connections @ University of Washington [unreadable] DESCRIPTION (provided by applicant): Depression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States, and are highly associated with exposure to stress. Impaired serotonin neurotransmission appears to be a central mechanism inducing depressive and anxiety symptoms. Previous studies have suggested that corticotropin releasing factor (CRF) receptor activation in the dorsal raphe, a major source of serotonin to the forebrain, is a critical mechanism underlying stress effects on serotonergic systems. However, the effects of CRF on dorsal raphe vary depending on dose, location within the nucleus, and receptor specificity. The origin of CRF projections to the dorsal raphe, and their potential to be regulated by dorsal raphe outputs is also unknown. Nor are the roles in stress response of the several neuropeptides increasingly recognized as co-transmitters with serotonin that may be involved in the effects of chronic stress. I will use a serotonergic cell line, RN46A-B14 to model the dose response and second messenger effects of CRF receptor activation on serotonergic neurons, helping to elucidate the direct effects of CRF there. Using a novel retrograde gene transfer system, canine adenovirus-2, 1 will determine the origins of CRF projection to the various subregions of the dorsal raphe, suspected to be the central nucleus of the amygdala and bed nucleus stria terminalis. I will also determine reciprocal projections of the dorsal raphe to these regions, delineating the circuitry that could underlie intrinsic neuromodulation, a phenomena that may underlie some of the long lasting behavioral alterations associated with stress. Finally, I will also produce a conditional knockout Tph2 transgenic mouse and determine the ability of a canine adenovirus-Cre recombinase vector to specifically alter serotonergic transmission in defined pathways. This methodology will allow me to separate the role of serotonin from the role of peptide co-transmitters in behavior. These studies will help develop technologies to understand the role of CRF projections to the dorsal raphe, and the role of dorsal raphe outputs in modulating circuits that underlie behavior related to anxiety and depression. The public health importance of this basic research is substantial. Understanding the mechanisms by which stress is communicated opens opportunities for intervening in this process. Given the role of stress in the development and recurrence of many psychiatric disorders, the ability to disrupt the communication of stress context would be a boon for both the treatment and prevention of many types of mental illness, including depression and anxiety disorders. This research will help provide the information necessary for the rational development of such interventions. [unreadable] [unreadable] [unreadable] |
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