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Functional interrogation of the role of PTP1B in Alzheimer's disease pathophysiology and sleep

Award Number: K99AG086335
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Functional interrogation of the role of PTP1B in Alzheimer's disease pathophysiology and sleep - PROJECT SUMMARY: Poor sleep has been identified as a major behavioral risk factor for Alzheimer's disease and related dementias (ADRDs) as well as a possible pathogenic factor driving disease progression. However, the molecular mechanisms linking healthy sleep to healthy brain aging remain elusive. Furthermore, we are yet to identify any drug that promotes healthy sleep or slows the progression of Alzheimer's disease. This is largely because the molecular mechanisms which govern both processes are yet to be fully understood. This project proposes to investigate the mechanisms that link sleep/wake regulation to Alzheimer's disease pathophysiology. To improve drug discovery for ADRDs, our lab has focused on targeting both age-associated and neuron-specific toxicities simultaneously. To this end, I established a drug screening pipeline to identify small molecules that delay aging and protect against neuronal cell death; we refer to these drugs as GeroNeuroProtectors (GNP). Using this pipeline, I identified CX08005 – an inhibitor of protein tyrosine phosphatase 1B (PTP1B) – as a candidate GNP which extends lifespan in C. elegans and protects hippocampal neurons from Alzheimer's disease-associated oxidative cell death. Notably, in addition to its anti-aging and neuroprotective effects, I find that CX08005 consolidates fragmented sleep/wake patterns in aged Drosophila. Thus, CX08005 may serve as a useful pharmacological tool to investigate the mechanisms that link sleep/wake regulation to Alzheimer's pathophysiology. In the proposed project, I will test the hypothesis that PTP1B activity is a central driver of Alzheimer's disease related sleep fragmentation and neurodegeneration. During the K99 phase, I will determine whether PTP1B inhibition improves Alzheimer's disease-associated outcomes and characterize the mechanisms of PTP1B signaling in modulating Alzheimer's disease related sleep disturbance. Aim 1 will determine whether PTP1B inhibition by CX08005 improves sleep/wake patterns, neuropathology, and cognitive performance in AD mouse models. Since the mechanisms of PTP1B-mediated geroneuroprotection are unknown, Aim 2 will apply CRISPR screening and tissue clearing and whole-brain labeling technologies to identify the genetic targets and brain regions modulated by CX08005 then determine which genes modulate sleep and lifespan. A portion of both aims will carry over into the independent R00 phase of the award. This work will lay the foundational groundwork necessary for future studies to investigate the translational potential of targeting protein phosphorylation and sleep to treat Alzheimer's disease and related dementias. The successful execution of the proposed training plan will prepare me to lead an independent research program.


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: 2025 ( Subtotal = -$8,489 )
2025	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	8/26/2025	TERMINATION	-$8,489
2025	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	5/29/2025	TERMINATION	$0
														Subtotal = -$8,489

Issue Date FY: 2024 ( Subtotal = $132,300 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	4/25/2024	NEW	$132,300
														Subtotal = $132,300

Grand Total All Awards = $123,811

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Functional interrogation of the role of PTP1B in Alzheimer's disease pathophysiology and sleep

Award Number: K99AG086335

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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