Saturday, May 18, 2024
5/18/2024
DESCRIPTION (provided by applicant): Drugs that block pro-inflammatory cytokines or their receptors such as Enbrel (a soluble TNF1 receptor) or Anakinra (a soluble IL-1 receptor antagonist) have been highly successful in treating autoimmune and inflammatory diseases such as rheumatoid arthritis (RA). However, many patients fail to respond to these therapies, and thus new approaches are still needed. A compelling new target is interleukin (IL)-17, the founding member of a novel family of inflammatory cytokines. The IL-17 family has strikingly little structural homology to better-known inflammatory cytokines such as TNF1 or IL-12. The IL-17 family has recently received considerable attention, because IL-17 and a close family member IL-17F are the hallmark cytokines of a newly-discovered T helper cell subset, Th17, that is distinct in lineage and function from the classic Th1 and Th2 cell populations. There is mounting evidence that Th17 cells cause pathology in autoimmune disease, including RA, EAE and colitis. IL-17 and IL-17F deliver signals through a ubiquitous, multimeric receptor complex composed of two IL-17 receptor superfamily members, IL-17RA and IL-17RC. Rational drug design requires a detailed understanding of the target molecule or pathway, but very little is known about the molecular nature of the IL-17R complex or its downstream signaling cascades. Therefore, the overall goal of this proposal is to achieve a detailed understanding of structure-function relationships in the IL-17R complex. To achieve this goal, we will probe the structure and function of the extracellular (Aims 1-2) and cytoplasmic domains (Aims 3-4) of individual subunits within the IL-17R complex. Aim 1: We recently reported that IL-17RA, the first known receptor subunit for IL-17, forms a multimeric complex that is pre-assembled in the membrane prior to ligand binding. This finding suggests that IL-17RA contains a pre-ligand binding assembly domain (PLAD), analogous to a similar domain in the TNF receptor superfamily. Building on preliminary data, we will delineate the IL-17RA PLAD in molecular detail (Aim 1A). Importantly, a soluble TNFR-PLAD serves as an effective inhibitor of arthritis in animal models. Therefore, we will evaluate whether an isolated IL-17RA-PLAD has similar pre-clinical potential as an inhibitor of IL-17 in vivo (Aim 1B). Lastly, we will evaluate the consequences of IL-17R blockade on oral thrush, a common opportunistic infection (Aim 1C). Aim 2: The composition of the IL-17R is surprisingly poorly defined. IL-17RC was recently shown to be a vital component of the IL-17R. We will define the stoichiometry of the IL-17R complex (Aim 2A) and evaluate interactions between IL-17RA and IL-17RC with or without ligand (Aim 2B). Aim 3: The mechanisms by which the IL-17R mediates signaling are largely unknown. However, we found that IL-17RA activates C/EBP transcription factors, which are necessary for target gene expression. We recently showed that IL-17 induces rapid phosphorylation of C/EBP2 on at least two sites. Aim 3 will focus on IL-17-induced pathways leading to C/EBP activation, by (i) defining regions in the IL-17RA tail required for activation of C/EBP (Aim 3A), and (ii) identifying kinases involved in C/EBP2 phosphorylation. Aim 4: The role of IL-17RC in signaling is undefined, and we will use our unique systems to define contributions of IL-17RC to signaling (Aim 4). Collectively, we will define the nature of the IL-17R, with the long-term goal of exploiting this knowledge for therapeutic benefit. PUBLIC HEALTH RELEVANCE The etiology of autoimmunity is poorly understood, but recent advances have discovered a secreted immune hormone (cytokine) termed IL-17 that appears to be responsible for causing many of the pathological effects of autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosis (SLE) and Crohn's disease. However, surprisingly little is known about how IL-17 causes these effects. This grant application is designed to understand the fundamental molecular biology of the cellular receptor for IL-17, which mediates all the effects of this cytokine on its target cells. Moreover, using that information, we aim to design specific blockers of the IL-17 receptor that might ultimately be used therapeutically to treat autoimmune conditions.
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