TLR/IL-1R signaling intermediaries and a target-specific therapeutic for arthriti

TLR/IL-1R 信号中介和关节炎的靶点特异性治疗

• 批准号: 8757788
• 负责人: AE-KYUNG YI
• 金额: $ 33万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757788
• 关键词: Adverse effects; Affect; Animal Model; Antigens; Arthritis; Autoimmune Diseases; Autoimmunity; Binding; Cartilage; Cell membrane; Cells; Chronic; Collagen Arthritis; Collagen Type II; Complex; Cytosol; Development; Dose; Drug Delivery Systems; Event; Experimental Animal Model; Experimental Arthritis; Experimental Models; Goals; Human; IRAK1 gene; IRAK4 gene; Immunization; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Joints; Knowledge; Ligands; MAP3K7 gene; Mediator of activation protein; Modeling; Molecular; Molecular Chaperones; Molecular Target; Mus; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Process; Protein Kinase; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; Reaction; Receptor Signaling; Recruitment Activity; Regimen; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Staging; Stream; Swelling; System; T-Lymphocyte; TRAF6 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Toll-like receptors; Toxic effect; Translating; Ubiquitination; base; bone; conventional therapy; design; in vivo; inhibitor/antagonist; innovation; insight; joint injury; macrophage; monocyte; nanoparticle; novel; novel strategies; prevent; protein kinase inhibitor; public health relevance; receptor

DESCRIPTION (provided by applicant): The objectives of this study are to understand the precise function of protein kinase D1 (PKD1) in the Toll- like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling pathway and to develop an effective and safe way to suppress the vicious cycle of inflammation in arthritic joints by interfering with TLR/IL-1R signal transduction using nanosome-based local delivery of inhibitory peptides. Rheumatoid arthritis (RA) is an autoimmune disease manifested by chronic inflammation, swollen joints, development of auto-reactive T-lymphocytes, and destruction of cartilage and bone in joints. While the factors that initiate and perpetuate inflammation are not well understood, it is thought that RA may be initiated in part by signaling through TLRs that contribute to the development of a self-perpetuating reaction leading to chronic inflammation and development of pathogenic auto-reactive Th1/Th17 cells. Therefore, disruption of the signaling pathway used by most TLRs may provide an opportunity to halt the RA process in the earliest stages of development before irreversible joint damage occurs. Preliminary studies show that systemic suppression of PKD1 activation substantially ameliorates arthritis in murine models. Also, that PKD1 is constitutively activated in RA synoviocytes and is responsible for expression of proinflammatory mediators by those cells. These findings support our hypothesis that PKD1 is a critical factor for development of proinflammatory reactions in the joint and might be an effective molecular target for therapeutic intervention. We have shown that following stimulation with MyD88-dependent TLR/IL-1R ligands, PKD1 (a serine/threonine kinase) is recruited to and activated within the cognate receptor complex. Activation of PKD1 in TLR/IL-1R signaling is down-stream of IRAK4 and IRAK1, but up-stream of TRAF6 ubiquitination. However, the specific domains of PKD1 that allow assembly of the receptor complex and the function of PKD1 in TLR/IL-1R signal transduction have not been established. Our goals are to define the molecular mechanism of PKD1 activation and action in TLR/IL-1R signaling, to identify the specific domains of PKD1 that allow for assembly of the IRAK4/IRAK1/PKD1/TRAF6 complex that can be applied to the development of a novel approach to inhibit PKD1 activation in a TLR/IL-1R pathway-specific manner, and to selectively deliver a therapeutic agent (that blocks TLR/IL-1R signal transduction) to the inflamed arthritic joints using an innovative target-specific drug delivery system. Specifically we will 1) determine the activation and action mechanisms of PKD1 in TLR/IL-1R signaling; 2) develop nanosomes that can deliver a therapeutic dose of peptide-based inhibitors of PKD1 activation to inflamed joints; and 3) test the hypothesis that delivery of a specific inhibitor of PKD1 activation targeted to inflammatory macrophages/monocytes will effectively alter the inflammatory milieu and prevent arthritis in an animal model. The results could be translated into an innovative therapeutic approach to effectively control RA progression with fewer side effects than current regimens.

描述（由申请人提供）：本研究的目的是了解蛋白激酶D1（PKD 1）在Toll样受体（TLR）/白细胞介素-1受体（IL-1 R）信号通路中的确切功能，并开发一种通过干扰TLR/IL-1 R信号转导来抑制关节炎关节中炎症恶性循环的有效安全方法 使用基于纳米体的抑制肽的局部递送。风湿性关节炎（RA）是一种自身免疫性疾病，表现为慢性炎症、关节肿胀、自身反应性T淋巴细胞的发展以及关节中软骨和骨的破坏。虽然引发和维持炎症的因素还不清楚，但据认为RA可能部分是通过TLR信号传导引发的，TLR信号传导有助于发展自我维持反应，导致慢性炎症和致病性自身反应性Th 1/Th 17细胞的发展。因此，大多数TLR使用的信号通路的中断可能提供在不可逆的关节损伤发生之前在发展的最早阶段停止RA过程的机会。初步研究表明，PKD 1活化的全身抑制可显著改善小鼠模型中的关节炎。此外，PKD 1在RA滑膜细胞中被组成性激活，并负责这些细胞表达促炎介质。这些发现支持了我们的假设，PKD 1是关节促炎反应发展的关键因素，可能是治疗干预的有效分子靶点。我们已经表明，MyD 88依赖性TLR/IL-1 R配体刺激后，PKD 1（丝氨酸/苏氨酸激酶）被募集到同源受体复合物中并在其中被激活。TLR/IL-1 R信号转导中PKD 1的激活位于IRAK 4和IRAK 1的下游，但位于TRAF 6泛素化的上游。然而，PKD 1的特定结构域，允许组装的受体复合物和功能的PKD 1在TLR/IL-1 R信号转导尚未建立。我们的目标是确定TLR/IL-1 R信号传导中PKD 1活化和作用的分子机制，以鉴定允许IRAK 4/IRAK 1/PKD 1/TRAF 6复合物组装的PKD 1的特异性结构域，所述复合物可用于开发以TLR/IL-1 R途径特异性方式抑制PKD 1活化的新方法，并使用创新的靶向特异性药物递送系统选择性地将治疗剂（阻断TLR/IL-1 R信号转导）递送到发炎的关节炎关节。具体来说，我们将1）确定TLR/IL-1 R信号传导中PKD 1的活化和作用机制; 2）开发可以将治疗剂量的PKD 1活化的基于肽的抑制剂递送到发炎关节的纳米体;和3）测试递送PKD 1活化的基于肽的抑制剂的假设。 靶向炎性巨噬细胞/单核细胞的PKD 1活化的特异性抑制剂将有效地改变炎性环境并预防动物模型中的关节炎。研究结果可以转化为一种创新的治疗方法，以有效控制RA进展，且副作用比当前方案更少。