Mapping ATP in microglial activation in vivo using genetically encoded reporters for MRI

Mikhail Shapiro, Ph.D.

California Institute of Technology

Funded in September, 2014: $100000 for 2 years


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New class of MRI agents may show how damaging inflammation occurs in brain injuries

The ultimate goal of this planned two-phase study is to use a novel MRI imaging agent to show, in living laboratory mice, how brain inflammation occurs and damages cells following brain injury. Phase I will establish the imaging approach’s feasibility.

The immune system is integrally involved in inflammation that damages cells following brain injury, yet scientists do not fully understand the molecular signals in the brain that initiate the inflammatory process. They do not yet have the capacity to image these molecular signals in living laboratory animal models. They do know that injured brain cells release the neurotransmitter ATP (adenosine triphosphate), and that ATP, therefore, is a key signal of cellular injury.

Moreover, studies indicate that ATP is among the most potent activators of immune “microglial” cells, which are the only immune cells that reside in the brain. ATP is also known to activate “astrocytes,” glial cells that have a major role in neural signaling in the brain. So scientists suspect that microglia and astrocytes are involved in initiating inflammation by sending signals to inflammatory immune T cells to enter the brain, but they need the capacity to image this signaling to determine how the process unfolds.

The capacity to undertake this signaling may now be within reach. Caltech investigators, who are creating a new class of genetically engineered molecular agents that “sense” specific molecules, have developed an agent that senses the ATP molecule and produces large changes in MRI signals.   The investigators hypothesize that their new imaging technique will demonstrate that when brain cells are injured and release ATP, the neurotransmitter signals microglia and astrocytes which then activate an immune system response that produces inflammation in the brain.  They aim to test this hypothesis in living laboratory animals, once they fully develop the MRI imaging agent and show in a live mouse model that MRI imaging signals change when the agent comes in contact with ATP that has been released by injured brain cells.

Once they demonstrate the feasibility of this new imaging technique, they will seek Phase II funding to map ATP release in a mouse model of traumatic brain injury and correlate it with microglial and astrocyte activation to recruit immune T cells into the brain. At the conclusion of the two-phase study, the findings are anticipated to be directly relevant to testing new types of experimental therapies to block damaging inflammation in humans with brain injuries.

Significance:   If this new MRI imaging technique reveals how signaling in the brain initiates an inflammatory process following brain injury, it may lead to development of new approaches to preventing inflammation by blocking this signaling.