Investigation of the Novel Role of 15-Hydroxyprostaglandin Dehydrogenase in Neurodegeneration in a Mouse Model of Alzheimer's Disease

About the Research Project
Program
Award Type
Postdoctoral Fellowship
Award Amount
$200,000
Active Dates
July 01, 2019 - June 30, 2022
Grant ID
A2019551F
Mentor(s)
Sanford Markowitz, MD, PhD, Case Western Reserve University
Andrew Pieper, MD, PhD, Case Western Reserve University
Goals
Alzheimer’s disease (AD) is one of the most highly prevalent and devastating conditions in society, and there are currently no treatments that prevent or slow disease progression. We have discovered a new biological system governing neurodegeneration in traumatic brain injury: enzymatic activity of 15-prostaglandin dehydrogenase in the brain that controls levels of prostaglandin E2, an endogenous agent that protects neurons. We also have preliminary evidence that levels of 15-PGDH are pathologically increased in animal models of AD, as well as human AD brain. This project will rigorously determine whether this aberrant increase in 15-PGDH plays a causative role in nerve cell death and behavioral learning problems in a mouse model of AD and could thus identify a new therapeutic target for patients.
Summary
Alzheimer’s disease (AD) is one of the most highly prevalent and devastating conditions in society, and there are currently no treatments that prevent or slow disease progression. Traumatic brain injury (TBI) is one of the strongest non-genetic risk factors for AD, and I have discovered a new biological system in the brain governing neurodegeneration in TBI: enzymatic activity of 15-prostaglandin dehydrogenase (15-PGDH). 15-PGDH activity degrades prostaglandin E2, an endogenous agent that is normally present to protect neurons. I have also discovered that levels of 15-PGDH are pathologically increased in animal models of AD, as well as in human AD brain. This project will rigorously determine whether the aberrant increase in 15-PGDH plays a causative role in nerve cell death and cognitive deficits in a mouse model of AD. If so, then inhibition of 15-PGDH with drugs related to the 15-PGDH inhibitor I am testing here could provide a new therapeutic agent to treat patients with AD, or to protect patients from developing AD after TBI.
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