Lipid Mediators In The Resolution of Asthma Exacerbations

该提案的长期目标是利用细胞粘附受体将药物分子靶向特定类型的细胞。短期目标是通过形成称为双功能肽抑制剂（BPI）的PLP-cIBR偶联物，将抗原（PLP 139 -151）和细胞粘附（cIBR-7）肽同时靶向抗原呈递细胞（APC）。PLP-cIBR已显示在小鼠模型中抑制实验性过敏性脑脊髓炎（EAE）的发展。中心假设是PLP-cIBR分子同时结合APC上的主要组织相容性复合物-II（MHC-II，I-As）和白细胞功能相关抗原-1（LFA-1），并抑制T细胞和APC之间界面处的“免疫突触”形成。在一项平行研究中，两种不同的BPI分子PLP-BPI和GAD-BPI分别抑制了SJL小鼠EAE和NOD小鼠1型糖尿病的进展。假设BPI分子靶向APC以抗原特异性方式改变T细胞的活化。如果这一假设得到证实，BPI分子在许多不同的自身免疫性疾病如类风湿性关节炎、狼疮和银屑病中诱导其他免疫耐受方面具有广泛的意义。在本项目中，我们将设计PLP-cIBR衍生物，通过改变接头、PLP肽和cIBR 7肽来增强体内活性并降低副作用。其次，将确定PLP-cIBR治疗的长期效果及其与其他抗原的交叉反应性。最后，将通过了解PLP-cIBR与APC表面上的MHC-II和LFA-1以及表达的受体的结合特性来评价PLP-cIBR的作用机制。

The long-term objective of this proposal is to utilize cell adhesion receptors for targeting drug molecules to a specific type of cells. The short-term objective is to simultaneously target both antigenic (PLP139-151) and cell adhesion (cIBR-7) peptides to antigen presenting cells (APC) by forming PLP-cIBR conjugate called bifunctional peptide inhibitor (BPI). PLP-cIBR has been shown to suppress the development of experimental allergic encephalomyelitis (EAE) in the mouse model. The central hypothesis is that the PLP-cIBR molecule simultaneously binds to the major histocompatibility complex-II (MHC-II, I-As) and leukocyte function-associated antigen-1 (LFA-1) on APC and inhibits "immunological synapse" formation at the interface between T cell and APC. In a parallel work, two different BPI molecules called PLP-BPI and GAD-BPI suppressed the progress of EAE in SJL mice and type-1 diabetes in NOD mice, respectively. The hypothesis is that targeting BPI molecules to APC alter the activation of T cells in antigenic specific manner. If this hypothesis is proven, BPI molecules have wide implications for inducing other immunotolerance in many different autoimmune diseases such as rheumatoid arthritis, lupus, and psoriasis. In this project, we will design PLP-cIBR derivatives to enhance the in vivo activity and lowering the side effects by altering the linker, PLP peptide, and cIBR7 peptide. Secondly, the long-term effects of treatment with PLP-cIBR and its cross-reactivity with other antigen will be determined. Finally, the mechanism of action of PLP-cIBR will be evaluated by understanding the binding properties of PLP-cIBR to MHC-II and LFA-1 on the surface of APC and the expressed receptors.