NIH – NIH Blueprint for Neuroscience Research: Dynamic Neuroimmune Interactions in the Transition from Normal CNS Function to Disorders (R01)

The goal of this initiative is to achieve molecular, cellular, and circuitry level understanding of the dynamic interactions of neuroimmune components in the temporal transition from normal central nervous system (CNS) function to disease conditions. Alterations of peripheral immune function and central neuroimmune signaling have been linked to a broad spectrum of disorders, such as neurological and neuropsychiatric disorders, degenerative diseases, addiction, pain, and obesity, as well as the aging process. Studies have shown that neuroimmune interactions are fundamental biological components of CNS function and dysfunction. Multiple CNS-resident cell types, such as microglia and astrocytes, dynamically detect the brain environment, regulate neuronal activity and neurocircuit function, and mediate neuroinflammatory responses through diverse activity states. Neuroimmune signaling mediated by these cell types is hypothesized to play an essential role in homeostatic regulation of normal neuronal activities, but also to contribute to pathophysiological states in the CNS by exerting damaging or reparative effects. Thus, glia cells, neurovascular units, as well as other neuroimmune components in the CNS, act as partners to neurons to maintain normal brain function and respond to challenges; as such, their neuroimmune signaling may play a crucial role in disease initiation and progression.

Previous findings have markedly advanced our knowledge of neuroimmune interactions in normal CNS function, neurodevelopment, and diseases. However, there is a lack of understanding of how dynamic changes in the multiple neuroimmune components mediate transitions from normal brain function to the early stages of CNS disorders, how changes in immune signaling are integrated into neuronal networks, and how disease progression is orchestrated by multiple neuroimmune components. A better understanding of dynamic interactions of neuroimmune components and the temporal transition to the disease process will provide a window into the early onset and progression of CNS disorders, which are poorly understood. Recent technological advances such as, but not limited to, measuring real-time gene and protein production in native environments, monitoring diverse cell phenotypes/states and cell-cell interactions, circuit-based multiplex profiling, as well as in vivo imaging of molecular and cellular components, have provided an unprecedented opportunity to track dynamic activity changes and generate snap shots of disease onset and progression at the molecular, cellular, and circuitry levels.

The outcomes of this initiative will define the role of multiple neuroimmune components in the transition from normal to disordered CNS function, which is critical for understanding disease onset and progression. In addition, gene and protein expression profiling of the temporal transition will define the time course of biomarkers and thus facilitate the design of effective therapeutic strategies for optimal timing at which therapies should be delivered.

This FOA will consider experimental paradigms of CNS disorders across all temporal scales, from disease onset through progression. It encourages projects that combine diverse expertise and use innovative approaches to generate an integrative understanding of dynamic changes in multiple neuroimmune components, such as neurons, microglia, and astrocytes, leading to pathophysiology at the molecular, cellular and circuitry level.

This initiative seeks applications in areas including, but not limited to:

  • Measuring of dynamic molecular and cellular activity changes in multiple neuroimmune components, such as neurons, microglia, and astrocytes, to define the role of each cell type in the transition from homeostatic interactions to disease onset and progression.
  • Examining how inflammatory signals, either arising within the CNS or the peripheral systems, alter the cross-talk among neuroimmune components, such as microglia, astrocytes, and neurons, and what their roles are in the dysregulation of specific neurocircuit function.
  • Determining of how the function of specific types of neurons or synapses are impacted by changes of neuroimmune signals or genetic alterations of neuroimmune components.
  • Examining how alterations of neuronal activity associated with diseases disrupt the homeostatic interactions of multiple neuroimmune components.
  • Examining how cell-type specific interference impacts the interaction of neuroimmune components and regulates the transition to pathophysiological CNS conditions.
  • Identifying molecular signatures of the critical time points at which alterations in neuroimmune interactions may promote or suppress disease onset or progression.

The focus of the FOA is on the dynamic neuroimmune interactions of multiple cell types in the CNS, including those of the retina, and their roles in the transition from normal to disease conditions. Projects studying how peripheral conditions or environmental factors alter neuroimmune interactions in the CNS will also be considered. Projects should address temporal changes in multiple neuroimmune components, such as neurons and glia cells, neurovascular units, or other relevant neuroimmune components. Studies that focus on infectious diseases or the pathophysiological conditions that arise from infiltrating T cells or B cells in the CNS are not responsive to this FOA. Projects measuring only one or two cell types, or the endpoint of diseases without tracking dynamic changes during the disease process will not be considered responsive to this FOA.

Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the goal of this FOA.

Deadline:  November 7, 2017 (letters of intent); December 7, 2017 (full proposals)