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.
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