Targeting CD28 ligand binding

靶向 CD28 配体结合

• 批准号: 8649027
• 负责人: JIM F Miller
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649027
• 关键词: Abbreviations; Accounting; Agonist; Amino Acids; Antigen-Presenting Cells; Avidity; Binding; Binding Sites; CD28 Antigens; CD28 gene; Cell Adhesion Molecules; Cell Surface Proteins; Cell membrane; Data; Extracellular Domain; Fluorescence Resonance Energy Transfer; Goals; Immunity; Immunoglobulins; Immunotherapeutic agent; Immunotherapy; Integrins; Knock-out; Ligand Binding; Ligands; Mediating; Mind; Modeling; Molecular Conformation; Monoclonal Antibodies; Mutation; Pharmaceutical Preparations; Play; Reagent; Regulation; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Solutions; T cell regulation; T cell response; T-Cell Activation; T-Cell Receptor; Tail; Testing; Variant; Work; abstracting; base; combinatorial chemistry; conformer; dimer; immunological synapse; immunological synapse formation; interest; molecular dynamics; novel; public health relevance; research study; response; small molecule

DESCRIPTION (provided by applicant): Project Summary / Abstract The two signal model and the concept of costimulation are well established in T cell regulation. Costimulation through CD28 can have a dramatic impact on many aspects of T cell activation, survival, tolerance, and differentiation. However, in spite of considerable interest and effort, the mechanisms of TCR and CD28 signal integration are not well understood. Our recent data indicate a novel site of regulation between TCR and CD28 signaling. We have found that TCR signaling can enhance CD28 ligand binding. Based on our preliminary data we have developed a model that TCR signaling induces a change in the orientation of the CD28 extracellular domains, allowing for bivalent binding. This increase in valency then accounts for the ability of TCR to enhance CD28 ligand binding. Although traditionally we think of CD28 as a modifier of TCR signaling, these results create a new paradigm for T cell activation, showing that TCR may also regulate CD28 function. In combination with the established role for TCR signaling in integrin activation, our results indicate that TCR may coordinate ligand binding for both the major costimulatory molecule (CD28) and the major adhesion molecule (LFA-1) during immunological synapse formation and T cell activation. This discovery of a novel regulatory mechanism in T cell activation identifies a new potential target for immunotherapy. With this goal in mind, we have developed experimental approaches that will directly test some of the predictions of this model and will use these reagents to identify new small molecules that can specifically modulate CD28 function, either as agonists, promoting effective T cell responses, or antagonists, inhibiting T cel responses. We will achieve these goals through two Specific Aims. 1. Generate structural mutations in the lumenal domain of CD28 that either lock CD28 in the low avidity form or stabilize the high avidity conformation. 2. Identify small molecule agonists and antagonists.

描述(由申请人提供)：项目摘要/摘要在T细胞调节中，两种信号模型和协同刺激的概念被很好地建立起来。通过CD28的共刺激可以对T细胞的激活、存活、耐受和分化的许多方面产生巨大的影响。然而，尽管有相当大的兴趣和努力，TCR和CD28信号整合的机制还不是很清楚。我们最近的数据表明，TCR和CD28信号之间存在一个新的调控位点。我们发现TCR信号可以增强CD28的配体结合。基于我们的初步数据，我们已经开发了一个模型，即TCR信号诱导CD28胞外结构域的取向改变，从而允许二价结合。这种价态的增加解释了TCR增强CD28配体结合的能力。虽然传统上我们认为CD28是TCR信号的修饰物，但这些结果为T细胞的激活创造了一个新的范式，表明TCR也可能调节CD28的功能。结合TCR信号在整合素活化中的作用，我们的结果表明，在免疫突触形成和T细胞激活过程中，TCR可能协调主要共刺激分子(CD28)和主要黏附分子(LFA-1)的配体结合。T细胞激活调控机制的发现为免疫治疗提供了一个新的潜在靶点。考虑到这一目标，我们开发了一些实验方法，将直接测试这一模型的一些预测，并将使用这些试剂来识别能够特异性调节CD28功能的新的小分子，无论是作为促进有效T细胞反应的激动剂，还是作为抑制T细胞反应的拮抗剂。我们将通过两个具体目标实现这些目标。1.在CD28的管腔结构域中产生结构突变，从而将CD28锁定在低亲和力形式或稳定高亲和力构象。2.鉴定小分子激动剂和拮抗剂。