Download To understand the dynamic interactions of multiple neuroimmune

NIH Blueprint Initiative, FY2018
Changhai Cui, Ph.D.
NIAAA, NIH
Normal brain function
•
•
•
•
Neural development
Neurogenesis
Synaptic function
Aging process
Brain dysfunction
•
•
•
•
•
Neurological disorders
Psychiatric disorders
Neuro- and retinal degeneration
Social behavioral deficit
Other disorders
To understand the dynamic interactions of multiple
neuroimmune components in the transition from
normal brain function to dysfunction at the molecular,
cellular, and circuitry levels
I. Multiple CNS-cell types in neuroimmune interaction and neuroinflammation
•
•
•
Cytokines
presynaptic
•
Cytokines
Chemokines
Neurotrophic
factors
neurotransmitters
spine
Microglia
Astrocyte
Kettenmann et al., 2013, Neuron 77, 10
Altered neuroimmune signaling in microglia and astrocytes have been
associated with a variety of CNS disorders.
See also: Chung et al., 2015. Nature Neuroscience. 18, 1539;
Columbo, E. and Farina, C. 2016. Trends Immunol. 37: 608-20
• Neural development
• Adult neurogenesis
• Synaptic interaction
Synapse formation
Astrocytes
Synapse elimination
Neurotransmission & plasticity
Microglia
(epilepsy & schizophrenia)
(AD, ASD, schizophrenia)
(ASD, schizophrenia)
Epilepsy, schizophrenia, Alzheimer’s disease, Autism spectrum disorders, and other
disorders
Chung, WS et al. (2015) Nature Neuroscience. 18, 1539–1545
Wake H. et al., Trends in Neurosciences 2013, (36) 209
Wu et al., 2015. Trends in Immunology. 36, 605
III. Immune regulation of neurocircuit function and dysfunction
Monoamine system
GABAergic
system
Glutamatergic system
DysphoriaAnhedonia
Depression
Social
behavior
Depression
AnxietyStress
Inflammatory
cytokines (IFNs,
IL-1b, IL-6 and
TNF)
Neurogenesis
Adapted from: Miller, AH and Raison, CL. 2016. Nature Reviews Immunology 16, 22–34
Falinano AN et al. 2016. Nature 535, 425–429
Ménard C. et al. 2016. Neuropsychopharmacology, 1–19
How does the transition from normal brain function to dysfunction
occur?
Neuroimmune
signaling / activity
• Neuroimmune factors
• Cell types
• Neurocircuits
Normal
function
Transition
Disease
conditions
To understand the dynamic interactions of multiple
neuroimmune components in the transition from
normal brain function to dysfunction at the molecular,
cellular, and circuitry levels
 Concurrent measurements of dynamic activity changes in multiple neuroimmune
components to define the role of each cell type in the transition from normal brain
function to disease onset and progression.
 Understand how inflammatory signals alter the cross-talk among neuroimmune
components, and what their roles are in the dysregulation of specific neurocircuit
function.
 Determine how the functions of specific types of neurons or synapses are impacted by
changes of neuroimmune signals or genetic alterations of neuroimmune components.
 Understand how alterations of neuronal activity disrupt the homeostatic interactions of
multiple neuroimmune components.
 Understand how cell-type specific interference impacts the interaction of neuroimmune
components and regulates transition to disease conditions.
 Identify molecular signatures of the critical time points at which alterations in
neuroimmune interactions may promote or suppress disease onset or progression.
 Integrative approach
• Combining neuroscience, neuroimmunology, novel techniques and
methods
• Leveraging technological advances to track changes of multiple
neuroimmune components
 Grant mechanism: Collaborative R01s
 Budget: 4.3 million total costs (FY2018)
 Expectation: 7 - 9 projects
 Outcomes
Integrative view of dynamic interactions of multiple neuroimmune
components in the transition from the normal brain function to
disease conditions
BP Neuroimmune Project Team
Soundar Regunathan (NIAAA)
Sangeeta Bhargava (NEI)
Francesca Bosetti (NINDS)
Richard Conroy (OD)
Nancy Desmond (NIMH)
Emmeline Edward (NCCIH)
Greg Farber (NIMH)
Woody Lin (NIDA)
Miroslaw Mackiewicz (NIA)
Jill Morris (NINDS)
Carol Pontzer (NCCIH)
Vasudev Rao (NIMH)
Denise Russo (NICHD)
Yolanda Vallejo-Estrada (NIDCR)
Andrew Weltz (NIBIB)
Yong Yao (NIMH)
Ursula Utz (NINDS)
George Koob (NIAAA)
Antonio Noronha (NIAAA)
Troy Zarcone (NIAAA)
Greg Farber (NIMH)
Alan Willard (NINDS)
Blueprint Coordinating Committee
Blueprint IC Directors