Project 4: Neuroprotection and neuroinflammation induced by the complement proteins and receptors In order to increase the successful identification of novel therapeutic targets for degenerative disorders commonly seen in the elderiy, the interrelations between new discoveries in genetics (GWAS identified risk association genes), cell biology (autophagy), immunology (inflammasomes) and neurobiology must be delineated using a combination of experimental approaches. One rapidly emerging area is the link between the immune system and cellular homeostasis in neurobiological systems, consistent with a role for the immune system components in normal and pathological brain function. The complement system is a powerful effector mechanism of the innate immune system that contributes to protection from infection and resolution of injury. Complement component deposition has been associated with Alzheimer's disease (AD), macular degeneration, Parkinson's disease and other age-related neurodegenerative disorders. While the activation of the complement cascade may be detrimental in these diseases, C l q , the initiator molecule of the classical complement pathway, has anti-inflammatory effects in the absence of the other components of the complement system. Unexpectedly, it has become apparent that in the brain C l q synthesis is induced in response to a variety of insults and injury initially in the absence of synthesis of other complement components. In addition, our lab made the novel observation that in vitro C l q improves neuronal survival under nutrient stressed conditions and suppresses amyloid beta-induced neuronal death suggesting that C l q may have a neuroprotective role. This novel neuroprotection triggered by C l q was associated with induction of expression of neuronal genes which if suppressed abrogated the C l q neuroprotective effects. Here we will collaborate with other members of the Program Project to identify the mechanisms of this C l q neuroprotection/survival, determine if this coordinates with a GWAS identified risk polymorphism in CRI, and create new animal models to elucidate the significance of this pathway in in vivo models of neurodegenerative diseases in aging populations. The molecular delineation of this novel pathway should uncover a number of potential therapeutic targets which have not been explored which can then be translated into innovative strategies (perhaps in combination with other therapeutic targets) in the clinic for the enhancement of neuron survival to improve the quality of life for individuals suffering from neurodegenerative or neurodevelopmental disorders.

Public Health Relevance

This project will identify key signaling pathways and molecular interactions that are required for a novel neuroprotection mechanism discovered in our laboratory and determine if this pathway improves neuronal survival in an animal model of Alzheimer's Disease (AD). In a complementary approach the biological basis of the AD risk association of a polymorphism in an immune regulatory protein, CRI, will be determined. These results will provide the first step in design of novel pharmacologic interventions for degenerative diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG000538-34A1
Application #
8705155
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-03-31
Support Year
34
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
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