Wednesday, February 5, 2025
2/5/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).