Research Project: Inhibition of NLRP3 inflammasome activation – a new strategy for prevention and treatment of Alzheimer’s Disease and late onset neurodegeneration.
The CART Fund will award Michael Karin Ph.D., University of California, San Diego School of Medicine, a 2017 research grant in the amount of $150,000. The grant will be awarded on May 16, 2017 at a meeting of The CART Fund in Orlando, FL.
Summary of Research Project
Alzheimer’s disease (AD) is the most common form of age-related dementia that exerts an incredible emotional and economic toll on our aging society. Currently, there are no effective treatments for AD or preventive measures that can delay its onset.
Recently, it has become clear that AD and other age-related dementias and cognitive impairments are associated with markers of inflammation. This has led to the hypothesis, which was adopted by our team, that neuroinflammation is the critical pathogenic mechanism connecting neuronal injury to cognitive impairment.
A key player in neuroinflammation is the “NLRP3 inflammasome”, a molecular machine composed of three proteins, the receptor/sensor NLRP3, the adaptor ASC and the effector caspase-1, which controls the production of IL-1β and IL-18, two immune system hormones (cytokines) that control the onset of neuroinflammation. Genetic ablation of the gene coding for NLRP3 in mice prevents age-related cognitive impairment, but effective pharmacological inhibitors of the NLPR3 inflammasome that can be used in the clinic are non-existent.
We have recently identified a new step in NLRP3 inflammasome activation that depends on the synthesis and activity of an enzyme called CMPK2. We will genetically ablate the CMPK2 gene in a mouse model of AD and determine whether this manipulation results in prevention of cognitive loss and amelioration of other AD symptoms. If CMPK2 ablation is curative we will embark on the development of new compounds that specifically inhibit CMPK2 enzymatic activity and will test them for their ability to prevent neuroinflammation and cognitive impairment in mouse AD models.
The Coins for Alzheimer’s Research Trust Fund (CART) is a project of the Rotary Clubs of North America. Founded in 1995 in Sumter SC, CART provides financial support for Alzheimer’s research projects that are yet to be supported by extensive preliminary data but have the potential to substantially advance biomedical research. Learn more at www.cartfund.org