None

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Neurological Disorders and Stroke (NINDS)

National Center for Complementary and Integrative Health (NCCIH)

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), with the National Institute of Dental and Craniofacial Research (NIDCR), National Center for Complementary and Integrative Health (NCCIH), and National Institute of Neurological Disorders and Stroke (NINDS), intends to promote a new initiative by publishing a Funding Opportunity Announcement (FOA) to solicit applications for research on Restoring Joint Health and Function to Reduce Pain (RE-JOIN) .

The goal of RE-JOIN will be to define the innervation of the different articular and peri-articular tissues that collectively form the joint (including bone, cartilage, synovium, joint capsule, ligament, tendon, fascia and muscle), by sensory neurons that mediate the sensation of pain. Knowledge about the types and distribution of neurites in joint tissues will facilitate the identification of key receptors and mediators that induce pain by activating specific sensory neurons. These mediators and their receptors will provide novel targets for reducing pain.

Research teams will map the sensory innervation of knee and/or temporomandibular joint tissues in animal models and/or human tissues and have the option of including additional joints. Research Teams may also further adapt or develop technologies that would improve the ability to map neurons in joint tissues.

Data harmonization, integration and visualization will require extensive coordination across teams. The goal will be to integrate data from the different teams to produce models of innervation in different joints.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.

The FOA is expected to be published in Winter 2022 with an expected application due date in Spring 2022.

This FOA will utilize the UC2 Clinical Trial Not Allowed activity code. Details of the planned FOA are provided below.

This Notice encourages investigators with expertise on joint components and structures, function, neurobiology and computer modeling to begin to consider applying for this new FOA.

The FOA will promote collaborative research projects conducted by teams using animal models and/or human tissue, and technology development to map the structural and functional characteristics of joint innervation.

Areas of research encouraged in this initiative are joint pain research, innervation mapping, neuroscience, neurovascular, tissue degeneration and arthritis, tissue regeneration, animal modeling, human tissue work, engineering, technology development research examining the mechanisms that underlie the effects of changes in joint tissue innervation healthy and arthritic disease, as well as research designed to improve the translation of existing knowledge of strategies for the prevention and treatment of joint pain.

Interdisciplinary, collaborative Research Teams will conduct exploratory and discovery projects and will apply current and emerging tissue technologies that probe the structural, functional, and molecular complexities of the sensory innervation of the joint in animal models, human tissues, or both. The focus of the project(s) for each Research Team will be the mapping of sensory neurons in one or more joints, with a primary focus on the knee and/or the temporomandibular joint, but the analysis of additional joints may be included. Research Teams may propose, as an optional element, the adaption or development of new technical approaches to mapping nerves in joint tissues. Research Teams are encouraged to propose methods for visualization of the nerves in the tissues of the joints.

Investigators will work collaboratively within the RE-JOIN Consortium on shared research objectives, data curation and harmonization efforts, and data visualization. This will allow comparisons of shared and unique innervation patterns across the joint types. In addition, the data generated by the different Research Teams will be integrated, to the extent possible, with common annotation and metadata, to produce a dataset for public access to enable the subsequent research and visualizations by the community, a key objective of RE-JOIN.

The RE-JOIN Program will produce:

• Maps with the location of the afferent neurites of dorsal root ganglia (DRG) and trigeminal ganglia (TG) sensory neurons involved in joint pain.
• Phenotype of the neurons that supply the joint tissues and the attribution of those neurites to specific types of neurons in the DRG and TG.
• A description of structural and functional changes in joint neurites with age and how these changes are influenced by sex, physical activity, etc.
• A description of changes in neurites accompanying degenerative and inflammatory changes in the joint.
• Identification of the structure, distribution and function of sympathetic neurons in the tissues and structures of the joint, and changes with joint degeneration and inflammation
• An improved understanding of joint-specific vs. shared patterns of changes in innervation with age or disease in different joint types.
• Validation of animal model maps in human tissue.
• Preliminary evidence for target identification of new treatments for joint pain.
• Large, annotated datasets and metadata to be shared under FAIR and Open Science principles.

The RE-JOIN Consortium will consist of the following key elements:

Research Projects focused on Mapping of Neurons in Joint Tissues

Projects will map the frequency and distribution of neurites from sensory neurons throughout the tissues and structures that comprise the joint; including dynamic changes in sensory neurite maps related to age, sex, physical activity, tissue degeneration and inflammation using animal models and/or human tissues.

Projects should focus on the knee and/or the temporomandibular joint. However, additional joints (e.g., other extremities and spine) may also be included.

Technology Adaptation and Development

Applicants will be encouraged, but not required, to advance the science and goals of RE-JOIN through the development or enhancement of innovative technologies and approaches. Technologies aimed at advancing the study of human joint innervation will be strongly encouraged. Technology development solely focused on the study of animal models should consider adaptation for use in humans.

Data Coordination and Integration

A Data Coordination Group will be funded separately for managing the data across the Consortium, including support for the sharing of data, models and analytical tools across projects; and including Consortium-wide definition of common data elements and data annotation. A key function of the Data Coordinating Group will be integration and knowledge management of the data produced by the Consortium.

Visualization

The Consortium will work together using the integrated datasets managed by the Data Coordinating Group to create maps or models or other means of visualizing the innervation of the structures and tissues of the joint, including commonalities across joint types.

Together the RE-JOIN Consortium will increase the understanding of the type and distribution of sensory neurons in different joint tissues; a first step in identifying treatment interventions via pharmacological and/or endogenous analgesic systems, in order to modulate the activation of these neurons to reduce joint pain, prevent the progression of joint deterioration, and ultimately, restore healthy joints. This includes understanding the factors leading to alterations in innervation and the pathways shared across different types of joints.