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Identification of novel phosphodiesterase (PDE)-modulating compounds and characterization of associated cytoprotective pathways in lightdamagedretina

Award Number: F30EY031566
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes ubiquitously expressed in the human body, and they play a critical role in a broad range of physiological processes, including regulation of the immune system, cardiovascular function, metabolism, reproduction, neurobiological processes of learning and memory, and vision. PDEs function enzymatically to hydrolyze intracellular cyclic nucleotide second messengers (cAMP and cGMP), thereby affecting various downstream cellular signaling pathways that control homeostatic processes. These include repair mechanisms that promote cell survival (somatic maintenance), as well as pro- apoptotic mechanisms that result in cell death. In aging and disease, dysregulation of these signaling networks can lead to a reduced investment in somatic maintenance, resulting in pathophysiological states of disease. However, as key regulatory nodes that modulate intracellular and subcellular concentrations of second messenger signaling molecules, it is conceivable that PDEs could be pharmacologically targeted in order to upregulate pathways that improve cellular viability in disease states. By integrating recent advances in PDE biology with high-throughput methods, this proposal aims to identify new PDE-targeting agents and further characterize the pathways through which they alleviate pathophysiology in chronic, debilitating disease. Specifically, our focus will be on the application of newly identified therapeutic agents to ameliorating disease in a mouse model of retinal degeneration. Our long-term goal is to obtain a better understanding of the role played by PDE-dependent signaling pathways in the pathogenesis of retinal degeneration and to develop interventions that stop the progression of human blinding diseases. Accordingly, we propose three thematically and experimentally linked Specific Aims, to: 1) identify novel PDE- modulating compounds through in silico screening, 2) evaluate the therapeutic efficacy of PDE-selective inhibitors in preventing retinal degeneration, and 3) validate a systems pharmacology approach to optimizing PDE inhibitor therapy. Successful completion of Aim 1 will result in the discovery of novel compounds that circumvent the limitations of existing PDE inhibitors and exhibit superior targeting selectivity with enhanced potential for clinical utility. Through completion of Aim 2, we intend to demonstrate a statistically significant therapeutic effect conferred by PDE inhibition that is robustly conserved across different mouse models of retinal degeneration. Lastly, successful completion of Aim 3 will dissect the underlying molecular mechanisms of cytoprotection in the context of stress-induced retinal degeneration, thereby providing innovative systems biology insights on the synergism between intersecting networks involving crosstalk among the many different cell types in the retina. Indeed, these insights will facilitate a more unified perspective to attain our long-term goal of developing new and improved pharmaceutical interventions to combat human blindness.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	4	12/4/2023	NON-COMPETING CONTINUATION	$52,694
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	4	6/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	3	12/19/2022	NON-COMPETING CONTINUATION	$51,752
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	3	3/8/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	002	2	6/1/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	2	1/18/2022	NON-COMPETING CONTINUATION	$51,036
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	2	5/12/2022	NON-COMPETING CONTINUATION	$717
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	002	1	3/17/2021	NEW	$0
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	1	3/17/2021	NEW	$516
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	1	12/9/2020	NEW	$50,520
														Subtotal = $51,036

Grand Total All Awards = $209,456

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Identification of novel phosphodiesterase (PDE)-modulating compounds and characterization of associated cytoprotective pathways in lightdamagedretina

Award Number: F30EY031566

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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