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High-probability grants
According to our matching algorithm, Douglas J. Sheffler is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2004 |
Sheffler, Douglas J |
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.). |
Interaction of Rsk2 With 5-Ht2a Receptor @ Case Western Reserve University
DESCRIPTION (provided by applicant): The goal of the proposed research is to verify the interaction of RSK2 with the third intracellular loop of the 5-HT2A receptor that was identified in a yeast-2-hybrid screen. Once this interaction has been established, its functional significance will be determined. Our central hypothesis is that RSK2 interacts with the 5-HT2A receptor, indicating a role in signal transduction. It is likely that this interaction plays a role in the ligand-dependent activation of the MAP Kinase cascade by the 5-HT2A receptor. Inactivating mutations in the RSK2 gene are responsible for the human Coffin-Lowry syndrome. This syndrome is characterized by severe non-specific mental retardation, psychosis, and progressive skeletal deformations. The psychosis that is present in Coffin-Lowry syndrome may prove to be attributed to a disfunction of 5-HT2A signaling. To test this central idea we propose to verify the interaction of the 5-HT2A receptor's third intracellular loop and RSK2 via coimmunoprecipitation studies and through confocal microscopy studies. The binding site of RSK2 to the 5-HT2A receptor will be defined via site-directed mutageneis studies in conjunction with 2-hybrid analysis. The functional role of the interaction between RSK2 and the 5-HT2A receptor will be defined.
|
0.948 |
2019 — 2020 |
Sheffler, Douglas J |
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. |
Lead Optimization of Novel Crfbp-Crfr2 Complex Modulators For Alcohol Use Disorder @ Sanford Burnham Prebys Medical Discovery Institute
Project Summary This R01 application entitled ?Lead Optimization of Novel CRFBP-CRFR2 Complex Modulators for Alcohol Use Disorder? is in response to PAR-17-336 ?Discovery of in vivo Chemical Probes for Novel Brain Targets (R01)?. In the United States, alcohol use disorder (AUD) affects 15.1 million adults over the age of 18 and is the 4th leading preventable cause of death. There remains a critical unmet need to develop more effective therapeutics to treat AUD. Stress is a significant component in the development and maintenance of AUD. Corticotropin releasing factor (CRF) plays an obligatory role in hypothalamic-pituitary-adrenal axis activation and subsequent release of glucocorticoids in response to stress. CRF exerts its effects by binding to two receptors (CRF1 and CRF2) and a 37 kD CRF binding protein [CRFBP (37kD)]. CRFBP plays a key role via CRF2 in the modulation of ethanol consumption through actions in the ventral tegmental area (VTA). We have demonstrated that CRF modulates synaptic input by potentiating N-methyl-D-aspartate-mediated excitatory postsynaptic currents through CRFBP/CRF2 interactions in this region. More recently, our data suggest a dual role for CRFBP where the CRFBP (27kD) fragment acts to terminate CRF effects and where the CRFBP (10kD) fragment has a potential excitatory function. These data support the hypothesis that CRFBP has functions beyond sequestering CRF and that its interaction with CRF2 may represent a novel target for the treatment of AUD. We developed and performed a novel high-throughput screen utilizing a tethered receptor complex between CRFBP (10kD) and CRF2 and identified novel, small molecule, CRFBP-CRF2 negative allosteric modulators (NAMs) that act noncompetitively with respect to CRF. These NAMs do not inhibit CRF2 in the absence of CRFBP (10kD) or inhibit CRF1. Our structure-activity-relationship studies led to the development of both lead and back-up CRFBP-CRF2 NAMs that are ready for full-scale chemistry optimization to provide compounds suitable for ex vivo studies. Thus, our overall objective is to develop orally active CRFBP-CRF2 modulators suitable for advanced in vivo proof-of-concept studies for the treatment of AUD. Our Specific Aims are: 1) Design and synthesize optimized CRFBP-CRF2 NAMs that are orally active in vivo; 2) Assess the potency and selectivity of CRFBP-CRF2 NAMs in relevant in vitro assays; 3) Profile the absorption, distribution, metabolism, and excretion (ADME) properties of CRFBP-CRF2 NAMs in vitro and pharmacokinetic (PK) properties in vivo; and 4) Characterize lead CRFBP-CRF2 NAM probes in ex vivo rodent models of AUD. The CRFBP-CRF2 NAMs generated will provide powerful tools for testing the role of the CRFBP-CRF2 interaction in vivo. More importantly, we are well-positioned to develop potent and selective small molecule CRFBP-CRF2 NAMs with optimized PK properties that will be utilized for in vivo proof-of-concept studies. This multidisciplinary research program has the potential for significant scientific and medical impact by contributing to the discovery of new medications for AUD.
|
0.909 |