Request for Information (RFI): Input on the Development of a Consortium for Signaling Networks to Critical Targets (“CONNECT”) in Rheumatoid Arthritis, Lupus and other Autoimmune Conditions

Notice Number: NOT-AR-14-012

Key Dates
Release Date: November 20, 2013
Response Date: December 16, 2013

Related Announcements

Issued by
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Allergy and Infectious Diseases (NIAID)


The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Allergy and Infectious Diseases (NIAID) are issuing this Request for Information (RFI) to solicit ideas and suggestions for the development of a team science research program that will provide investigators with the resources needed to elucidate key molecular signaling networks in disease tissues, as well as circulating cells, in human beings. The work will initially focus on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), with the development of an approach applicable to other autoimmune diseases. The goal is to achieve a systems-level understanding of gene expression and signaling in subsets of target tissues and blood cells to define shared and disease-specific biological pathways and allow identification of signaling pathways that will lead to the identification of high-value relevant drug targets.

The NIH also plans to hold a webinar to discuss this RFI with members of the public and research community.  Information regarding the webinar will be posted at on or about November 27, 2013.


In recent years, the ability to target specific immunological cells or inflammatory mediators (cytokines) has resulted in significant advances in treatments for autoimmune diseases.  However, the clinical benefit achieved so far is limited. In RA and juvenile idiopathic arthritis, current biotherapeutic drugs reduce disease activity by approximately half in half the patients, and a majority of the remaining patients respond poorly to subsequent drugs. In other diseases such as SLE, no effective targeted therapies exist for the most severe forms of the disease including central nervous system lupus and lupus nephritis.  The experience in RA and several other disorders shows that targeting inflammation and the immune system can lead to successful treatments. However, developing new targeted therapies that can achieve a high degree of disease activity reduction (i.e., remission) or cure disease, with fewer immunosuppressive side effects, remains a major challenge.  Furthermore, there has been a very high failure rate among drug targets identified from studies in mouse models; for example, all targets tested so far for lupus nephritis have failed in human trials.  As a result, there is a critical need to study tissue from humans with autoimmune diseases directly to identify the aberrant immunological pathways and their regulators in order to reveal new, directly implicated drug targets in humans.  Major target tissues for RA (e.g., synovial tissue) and SLE (e.g., kidney and skin) can be biopsied, and emerging technologies allow for a detailed analysis of even small amounts of tissue, down to the single cell level.

The NIH is considering supporting an innovative research resource infrastructure to achieve this goal in RA and SLE. The overarching vision is that these detailed discovery studies will identify (and subsequently validate in vitro) key targets that regulate the pathways that drive the diseases. The concept is that these pathways function as modules that are differentially regulated in autoimmune diseases. Drugs developed for a particular module are likely to have efficacy in other diseases where similar perturbations of that module are found.

Towards this goal, a consortium of clinical centers will be organized to recruit and characterize relevant RA and lupus cohorts to obtain tissue samples (e.g., synovium and kidney, respectively, with concurrent peripheral blood) of adequate quality to permit discovery research by a group of collaborating technology centers. These centers will use novel and emerging analytic assays, such as deep RNA sequencing of tissue at the single cell level; detection of methylation, histone modifications, and DNase hypersensitivity sites in specific cell subsets of interest to look for epigenetic changes; multiparameter cell phenotyping and phospho-flow analysis using mass spectrometry approaches such as CyTOF (time-of-flight mass cytometry), etc.  Associated patient-level data might include genetics, metabolomics, and analysis of the microbiome.  A bioinformatics resource center is expected to be included to develop and provide an integrated informatics solution that enables data accrual, storage, catalog, and analysis as well as a portal for dissemination of data and information.  This portal would provide the research community with a resource to access integrated information on cells in the blood and tissue in RA and SLE patients at a molecular level, which would enable (1) deconstruction of diseases mechanisms; (2) identification of disease modules and signaling pathways involved in clinical response; and (3) targeting of key signaling pathways for development of new therapies.

Information Requested

In order to maximize the impact of this valuable community resource, and facilitate its use by scientists with a broad range of expertise, we seek input on the following areas; however, your input is not limited to these areas:

  • Assembling relevant patient cohorts who would consent to participate;
  • Identification of subsets of patients and recruitment strategies;
  • Identification of existing resources that could be used;
  • Approaches for obtaining high-quality tissue specimens, including research infrastructure that would be needed, and the advantages of different techniques (e.g., mini-arthroscopy with shaver biopsy, ultrasound-guided needle biopsy, tissue fragments obtained from synovial fluid, and others); 
  • Preferred models for working with a Central Institutional Review Board (Central IRB);
  • The availability, reliability and value of technologies for analysis of single or small populations of cells, as well as other emerging technologies (“omics”), which could be used to develop a genome-wide molecular disease knowledge base;
  • Functionalities/query tools that would be desirable in a community-based web portal to be constructed and linked to data both created by this research infrastructure and imported from other sources;
  • Automated computational tools that would allow investigators to better integrate and perform systems-level analysis of datasets; and
  • Any other relevant autoimmune diseases and patient subset populations where the approach described above is most urgently needed and feasible. 

Submitting a Response

All responses must be submitted to by December 16, 2013.  Please include the Notice number NOT-AR-14-012 in the subject line. Response to this RFI is voluntary. Responders are free to address any or all of the categories listed above. The submitted information will be reviewed by the NIH staff. Submitted information will be considered confidential.

This request is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government or the National Institutes of Health (NIH). The NIH does not intend to make any awards based on responses to this RFI or to otherwise pay for the preparation of any information submitted or for the Government's use of such information.

The NIH will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder’s submission. However, responses to the RFI may be reflected in future solicitation(s). The information provided will be analyzed and may appear in reports. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information received or provide feedback to respondents with respect to any information submitted.  No proprietary, classified, confidential, or sensitive information should be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).


Please direct all inquiries to:

Su-Yau Mao, Ph.D.
Division of Skin and Rheumatic Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-5032

Yan Wang, M.D., Ph.D.
Division of Skin and Rheumatic Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-5032