NIH – Ocular Surface Innervation from Cell Types to Circuit Functions (U01 Clinical Trial Not Allowed)

December 17, 2021 by


The NEI has launched the Anterior Segment Initiative (ASI) in order to capitalize on research opportunities at the front of the eye. The anterior segment includes the cornea, iris, ciliary body, and ocular lens. Disruptions in the health of the anterior segment manifest in a variety of ways including dry eye disease, ocular pain, Sjogren’s syndrome, migraine, and uveitis. The NEI has supported both basic and clinical research in these areas and significant progress has been made. Scientific advances in areas such as ocular imaging present exciting research opportunities.

There are significant knowledge gaps in understanding the role the nervous system in maintaining the health of the anterior segment and how disruption of normal nervous system functioning contributes to disorders and disease such as ocular surface pain, itch, inflammation, dry eye and other neurological symptoms such as migraine and photophobia.  Unpleasant ocular sensations substantially decrease a patient’s quality of life by interfering with activities of daily living. Options for effective treatment and long-term relief of these conditions are currently limited.

Dissecting ocular sensation and tearing circuits is integral to understanding the processes that contribute to and result from certain types of disease, infection, and trauma.  These processes may be at the level of the peripheral nervous system (PNS) or the central nervous system (CNS). PNS sensitization and plasticity may involve the corneal afferent nerve terminals and surrounding tissues. CNS sensitization that leads to chronic conditions may involve the trigeminal nuclei and thalamus and/or higher brain centers. In addition to the ascending pathways, descending pathways are also important to anterior segment homeostasis and disease mechanisms.

The purpose of this FOA is to gain a comprehensive understanding of the neuronal cell types, cell-to-cell interactions and peripheral and central neural circuitry involved with normal anterior segment homeostasis as well as the changes in these pathways that contribute to disease and abnormal sensations.


The objective of this RFA is to develop a comprehensive understanding of the afferent and efferent neuronal pathways in the anterior segment of the eye that subserve ocular pain and tearing at the anatomical, cellular and functional levels. This research will also provide a foundation for understanding the role of ocular surface sensation in the development of other disorders such as itch, migraine and photophobia, with the long-term goal of advancing translational and clinical research on the anterior segment of the eye to improve ocular health.

It is expected that applicants will assemble multidisciplinary Research Teams to address important questions related to anterior segment innervation. Research Teams funded under this initiative are expected join in a consortium to share ideas, technology, and data at the earliest stages of their individual projects. Each Research Team is expected to meaningfully address at least two of the following levels of research and analysis:

1. Anatomy/morphology - the research objectives may include but are not limited to:

  • Anatomical characterization including cell spatial location and morphology (e.g., cell size, shape, dendritic arborization)

  • Mapping long- and short-distance neuronal connectivity

  • Identifying input and output neurons and their projections (e.g., using retrograde and anterograde viral tracings), as well as the local circuit neurons and their connections

  • Determining the location and prevalence of non-neuronal cell types

  • Examining innervation patterns in normal corneas versus acute and chronic pain and/or dry eye disease

2. Cellular/molecular properties – the research objectives may include but are not limited to:

  • Characterizing cell classes and types based on single-cell transcriptome signatures

  • Identifying cell types using immunohistochemistry and immunocytochemistry approaches

  • Using single cell epigenome approaches (e.g., chromatin accessibility, DNA methylation) to define cell types

  • Molecular characterization of primary afferents including mechanoreceptors, chemoreceptors, thermoreceptors and nociceptors

  • Identifying neurotransmitters at synaptic junctions

  • Discovering the molecular composition of non-neuronal cell types

3. Functional properties – the research objectives may include but are not limited to:

  • Determining the polymodal stimulus/response properties of identified neurons

  • Identifying patterns of activity and interactions across functionally connected neurons

  • Characterizing functional connectivity motifs across local circuits and long ranging networks

  • Identifying factors that regulate and/or disrupt normal circuit activity

  • Examining the functional impact of perturbing normal circuit activity

  • Characterizing the bidirectional communication between sensory afferents and non-neuronal cells and tissues

Building upon and incorporating previously established knowledge and atlases are highly desirable. Artificial Intelligence/ Machine Learning/ Deep Learning approaches for informatics, data mining, and integrating knowledge (established and newly acquired) across the three levels of analysis are encouraged.

Key Dates:

Open Date (Earliest Submission Date): February 07, 2022
Letter of Intent Due Date(s): February 7, 2022
Application Due: March 7, 2022

URL for more information:

Filed Under: Funding Opportunities