The ACE Collaborative Project is systematically integrated with the Principal Project (Robinson), Pilot Project (Chang), and HIMC (ACE Core B, Maecker). The broad, long-term goal of the Collaborative Project is to develop protein and peptide arrays for use in mechanistic assays in multiple ACE trials and for other ACE Centers to employ as part of their basic science projects. There are 3 specific aims.
Aim 1 will develop a peptide array platform co-developed with Intel, Inc. for characterizing linear epitopes of histones targeted by autoantibodies.
Aim 1 A and IB will develop peptide arrays forthe other 4 histone linear tails for use in Aims 2 and 3.
Aim 1 C will use non-fluorescence-based detection with Giant MagnetoResistive (GMR) sensors to improve sensitivity and move toward a method that could enable real-time, multiplexed measurements.
Aim 2 will test specific hypotheses related to autoantibodies and autoimmunity.
In Aim 2 A we will test the hypothesis that specific autoantibodies are associated with unique transcript profiles;
Aim 2 B will study patients who are flaring, and Aim 2C will analyze disease subsets.
Aim 2 D will explore the functions of the autoantibodies, e.g. their ability to block or activate cytokine, growth factor, or other receptors, or to form immune complexes (ICs) that can influence toll like receptor (TLR) signaling. The Principal Project (Robinson) will clone and express monoclonal antibodies directed against cytokines and other autoantigens, then use the antibodies to determine affinity, cross-reactivity, and function in ICs.
Aim 3 will test the hypothesis that autoantibody and B cell repertoires change in response to therapeutic interventions including inhibitors of TNF, BAFF, IL-6, JAKs, and IL-1. We will test the hypothesis that a subset of autoantibodies will be affected by successful treatment, and that this will correlate with alterations in the B cell repertoire (Principal Project, Robinson), the epigenome (Pilot Project, Chang), cellular signaling pathways measured by CyTOF (HIMC ACE Core B, Maecker), and cytokine/chemokine levels themselves (HIMC ACE Core B, Maecker). Protein and peptide arrays will be an integral component of the ACE Shared Research Agenda.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI110491-01
Application #
8732974
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Lee, Jung-Rok; Sato, Noriyuki; Bechstein, Daniel J B et al. (2016) Experimental and theoretical investigation of the precise transduction mechanism in giant magnetoresistive biosensors. Sci Rep 6:18692
Rosenberg, Jacob M; Price, Jordan V; Barcenas-Morales, Gabriela et al. (2016) Protein microarrays identify disease-specific anti-cytokine autoantibody profiles in the landscape of immunodeficiency. J Allergy Clin Immunol 137:204-13.e3
Lee, Jung-Rok; Bechstein, Daniel J B; Ooi, Chin Chun et al. (2016) Magneto-nanosensor platform for probing low-affinity protein-protein interactions and identification of a low-affinity PD-L1/PD-L2 interaction. Nat Commun 7:12220
Lee, Jung-Rok; Haddon, D James; Wand, Hannah E et al. (2016) Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus. Sci Rep 6:27623
Robinson, William H; Mao, Rong (2016) Biomarkers to guide clinical therapeutics in rheumatology? Curr Opin Rheumatol 28:168-75
Slight-Webb, Samantha; Lu, Rufei; Ritterhouse, Lauren L et al. (2016) Autoantibody-Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity. Arthritis Rheumatol :
Rasmussen, Tue Kruse; Andersen, Thomas; Bak, Rasmus Otkjær et al. (2015) Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus. Arthritis Res Ther 17:154
Robinson, William H; Mao, Rong (2015) Decade in review-technology: Technological advances transforming rheumatology. Nat Rev Rheumatol 11:626-8
Robinson, William H (2015) Sequencing the functional antibody repertoire--diagnostic and therapeutic discovery. Nat Rev Rheumatol 11:171-82
Kattah, Nicole H; Newell, Evan W; Jarrell, Justin Ansel et al. (2015) Tetramers reveal IL-17-secreting CD4+ T cells that are specific for U1-70 in lupus and mixed connective tissue disease. Proc Natl Acad Sci U S A 112:3044-9

Showing the most recent 10 out of 17 publications