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Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation

研究 SLC 转运蛋白在炎症中的作用的化学蛋白质组学策略

基本信息

批准号：
10686379
负责人：
Christopher G Parker
金额：
$ 68.51万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686379
关键词：
Adaptive Immune System Address Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes Binding Biochemical Biology CCL21 gene Cells Chemicals Clinical Collaborations Crohn&apos s disease Dedications Dendritic Cells Detection Development Disease Disease model Endosomes Environmental Risk Factor Evaluation Event Foundations Functional disorder Future Gene Family Genetic Genetic study Goals Hematopoietic Homeostasis Human Immune Immune System Diseases Immune response Immunology Impairment Infection Inflammation Inflammatory Inflammatory Response Innate Immune System Interferon Type I Interferon alpha Interferons Intervention Invaded Investigation Knowledge Lead Ligands Lupus Macrophage Mass Spectrum Analysis Mediating Membrane Metabolic Methodology Molecular Mus Nucleic Acids Pathogenesis Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Process Production Proteins Proteomics Reporting Role Series Signal Induction Signal Transduction Signaling Protein Site Small Inducible Cytokine A21 Systemic Lupus Erythematosus TLR7 gene TNF gene Therapeutic Toll-like receptors Virus Diseases autoimmune inflammation autoimmune pathogenesis chemoproteomics cytokine genetic approach human disease immunogenic improved in vivo in vivo Model inhibitor innovation insight loss of function lysosomal proteins member mouse model novel novel strategies pathogen pharmacologic protein function protein protein interaction sensor side effect small molecule solute stem therapeutic target tool

项目摘要

PROJECT SUMMARY The innate immune system is the first line of defense against invading pathogens and intimately collaborates with the adaptive immune system to maintain physiological homeostasis. However, components of the immune response can sometimes become dysfunctional, failing in this protective role and even directly causing a variety of autoimmune diseases. Immune dysfunction arises from an interplay of genetic and environmental factors, however a mechanistic understanding of the various proteins and pathways that drive these conditions remains incomplete. In particular, it is known that immune sensors, which are typically dedicated to protection against infection, are sometimes usurped, and instead initiate and propagate autoimmune diseases such as systemic lupus erythematosus (SLE) and Crohn’s disease. Specifically, self-induced signaling by nucleic acid-sensing endosomal Toll-like receptors (TLRs 7 and 9) and the unchecked production of pro-inflammatory cytokines (e.g. type I interferons; IFN-I) in plasmacytoid dendritic cells (pDCs) are key events in the pathogenesis of numerous autoimmune conditions. Thus, compounds that can suppress the production of these cytokines in pDCs would be clinically useful agents for the treatment of such diseases. Recently, loss-of-function studies of the poorly characterized endolysosomal solute carrier gene family 15 member 4 (SLC15A4) in lupus mouse models revealed significantly reduced disease manifestation as well as near complete suppression of TLR7/9-mediated production of IFN-I and other proinflammatory cytokines. In this application, we have leveraged our lab’s innovative chemoproteomic fragment-based ligand discovery platform to develop a suite of chemical probes that engage SLC15A4 in human pDCs, block SLC15A4 mediated transport, and suppress IFN-I production in human and mouse primary pDCs. We will utilize an interdisciplinary strategy that draws upon the fields of chemical biology, immunology and mass spectrometry to illuminate how SLC15A4 controls TLR-mediated production of IFN-I in primary human and mouse immune cells and evaluate pharmacological inhibition in vivo. Specifically, we will investigate the effects of SLC15A4 pharmacological inhibition on endolysosomal homeostasis, on the protein interaction network of SLC15A4 and on signaling in immune cells crucial to autoimmune pathophysiology. Critically, we will assess the therapeutic potential of SLC15A4 in disease models of inflammation, such as lupus. The chemical tools generated, and knowledge gained from these studies are certain to greatly advance our understanding of SLC15A4 biology, enabling the identification of novel strategies to treat human autoimmune diseases.

项目总结先天免疫系统是抵御入侵病原体的第一道防线，并密切协作。与适应性免疫系统一起维持生理动态平衡。然而，免疫的成分反应有时会变得功能失调，无法发挥这种保护作用，甚至直接导致各种自身免疫性疾病。免疫功能障碍是由遗传和环境因素相互作用引起的，然而，对驱动这些条件的各种蛋白质和途径的机械性理解仍然存在不完整。具体地说，已知免疫传感器通常专用于保护感染，有时会被篡夺，相反，会引发和传播自身免疫性疾病，如系统性疾病红斑狼疮(SLE)和克罗恩病。具体地说，通过核酸传感的自我诱导信号内体Toll样受体(TLR7和TLR9)和不受抑制的促炎细胞因子的产生(例如血浆细胞样树突状细胞(PDCs)中的I型干扰素(IFN-I)是许多自身免疫性疾病。因此，能够抑制pDC产生这些细胞因子的化合物将成为治疗此类疾病的临床有用药物。最近，对功能丧失的研究较差狼疮小鼠模型中溶质载体基因家族15成员4(SLC15A4)的特征疾病表现显著减少，TLR7/9介导的TLR7/9几乎完全抑制产生干扰素-I和其他促炎细胞因子。在此应用程序中，我们利用了我们实验室的创新的基于化学蛋白质组片段的配体发现平台，以开发一套化学探针，使SLC15A4与人pDC结合，阻断SLC15A4介导的转运并抑制人干扰素-I的产生和小鼠原代PDCs。我们将利用利用化学领域的跨学科战略。生物学、免疫学和质谱学阐明SLC15A4如何控制TLR介导的人和小鼠原代免疫细胞中的干扰素-I，并评价体内的药理抑制作用。具体来说，我们将研究SLC15A4药物抑制对内溶酶体动态平衡的影响。 SLC15A4的蛋白相互作用网络和免疫细胞中对自身免疫病理生理至关重要的信号转导。关键的是，我们将评估SLC15A4在狼疮等炎症疾病模型中的治疗潜力。从这些研究中产生的化学工具和获得的知识肯定会极大地推动我们的对SLC15A4生物学的了解，使确定治疗人类自身免疫的新策略成为可能疾病。