New MRI agent may reveal how brain injury produces inflammation and how to prevent it

Mapping ATP Involvement in Neuroinflammation In Vivo Using Genetically Encoded Reporters for Magnetic Resonance Imaging

Mikhail Shapiro, Ph.D.

California Institute of Technology

Funded in December, 2016: $100000 for 2 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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New MRI agent may reveal how brain injury produces inflammation and how to prevent it

Investigators will explore in a laboratory mouse model of brain injury how the damaging process of inflammation occurs following injury. Their exploration utilizes a new MRI agent that they developed and validated through their $100,000 2014 Phase I award from the Foundation.   

The immune system responds to brain injury from trauma or stroke by mounting an inflammatory response that further damages brain cells at and around the injury site. What activates this brain inflammation, and can it be prevented? While scientists do not currently know how inflammation processes are initiated, they do know that damaged brain cells release a molecule called ATP (adenosine triphosphate), which stores energy required by all cells. 

The investigators have hypothesized that ATP release produces inflammation by activating one or both of two types of cells in the brain:  1) immune microglia cells, which help to activate and direct immune responses; and 2) star-shaped cells called “astrocytes” that send signals that can be protective or harmful to neural networks.  Until now, researchers have not imaged ATP release from injury-damaged brain cells to visualize the signaling processes that lead to inflammation.

The Caltech investigators sought to do so by developing a genetically encoded MRI imaging agent that would bind to ATP.  That invasive approach failed. Instead, though, they found that the MRI imaging agent manganese, a mineral element in enzymes, successfully binds to ATP and does so non-invasively. This ability of the manganese imaging agent to sense ATP signals had not been previously observed.  So using this MRI imaging agent, the investigators will, for the first time, be able to determine how ATP is released by injury-damaged brain cells and initiates inflammation in the laboratory mouse model of head injury.

In this Phase II study, they first will map ATP release. Then they will examine the effect of injury-induced ATP release on microglial and astrocyte activation. They will determine how either or both microglial cells and astrocytes send signals that ultimately recruit immune “T cell” antibodies to enter the brain to mount an inflammatory response. Then they will correlate their MRI imaging results with studies of the laboratory animals’ autopsied brain tissues to see how these signaling processes generate damaging inflammation. The findings are anticipated to lead directly to clinical studies of experimental therapies designed to block the deleterious signaling.

Significance:   Results may lead to new ways to prevent harmful inflammation that compromises recovery in people who have sustained a brain injury.     

 

 

ABSTRACT

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Mapping ATP Involvement in Neuroinflammation In Vivo Using Genetically Encoded Reporters for Magnetic Resonance Imaging

Neuroinflammation is increasingly appreciated as an important factor in neurological conditions ranging from acute brain injury to long-term neurodegeneration. However the molecular signals underlying neuroinflammatory processes are not fully understood, partly because it is currently difficult to monitor such signals inside the brains of living animals. To overcome this limitation, we will develop a transformative technology for high-resolution non-invasive neurochemical imaging and use it to map the release of adenosine triphosphate (ATP) as a signal of cellular injury during brain trauma. Our approach makes use of a new class of reporters for magnetic resonance im-aging (MRI) developed in our laboratory, which we will target to the extracellular space of the brain. This will allow us to image the ATP levels encountered by cells such as microglia and as-trocytes during brain injury in live animals, and correlate it with histological markers of microglial and astrocytic activation and immune cell recruitment. Via three specific aims, we will: (1) com-plete the development of MRI reporters of ATP, (2) demonstrate in vivo imaging of ATP expo-sure, and (3) map ATP release in a model of traumatic brain injury and its correlation with glial activation and immune cell recruitment. Successful completion of this research will result in an enhanced understanding of the spatial and temporal dynamics of ATP and microglial and astro-cyte activation in brain injury and demonstrate the utility of a new technology for neurochemical imaging with widespread applications in neuroscience. The resulting insights could aide in the development of better treatments for neurological trauma and inflammation, and enable future work on a new class of molecular diagnostics.

INVESTIGATOR BIOGRAPHIES

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Mikhail Shapiro, Ph.D.

Mikhail Shapiro is an Assistant Professor of Chemical Engineering and a Heritage Principal Investigator at the California Institute of Technology. His research is focused on the development of technologies to image and control biological function non-invasively at the molecular level. Dr. Shapiro received his PhD in Biological Engineering from the Massachusetts Institute of Technology and his BSc in Neuroscience from Brown. He conducted post-doctoral research in biophysics at the University of Chicago and was a Miller Fellow at the University of California, Berkeley. Dr. Shapiro developed the first genetically engineered functional sensors for magnetic resonance imaging of the brain, discovered fundamental mechanisms by which infrared light stimulates neurons, and introduced the first protein-based molecular imaging agents for ultrasound. He has been awarded the Hertz, Soros, Miller and Life Science Research Foundation fellowships, the Hertz PhD Thesis Prize, the Burroughs Wellcome Career Award at the Scientific Interface, the DARPA Young Faculty Award, the Pew Scholars Award, the Sontag Foundation Distinguished Scientist Award, the Packard Fellowship for Science and Engineering and the Technology Review TR35 award for top innovators under age 35.

KEYWORDS


Conditions: Brain injury
TBI
Technology: MRI