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 /摘要两个信号模型和共刺激的概念在T细胞调节中已很好地确定。通过CD28进行共刺激会对T细胞激活，生存，耐受性和分化的许多方面产生巨大影响。然而，尽管有很大的兴趣和努力，但TCR和CD28信号积分的机制尚不清楚。我们最近的数据表明TCR和CD28信号之间的调节部位新颖。我们发现TCR信号可以增强CD28配体结合。基于我们的初步数据，我们开发了一个模型，该模型可导致CD28细胞外域的方向发生变化，从而允许双重结合。价值的增加，然后说明了TCR增强CD28配体结合的能力。尽管传统上我们认为CD28是TCR信号的修饰符，但这些结果为T细胞激活创造了新的范式，表明TCR也可能调节CD28功能。结合TCR信号在整联蛋白激活中的既定作用，我们的结果表明，TCR可以在免疫突触形成和T细胞活化过程中协调主要共刺激分子（CD28）（CD28）和主要粘附分子（LFA-1）的配体结合。 T细胞激活中一种新型调节机制的发现确定了免疫疗法的新潜在靶标。考虑到这个目标，我们开发了实验方法，这些方法将直接测试该模型的某些预测，并将使用这些试剂来识别可以特异性调节CD28功能的新小分子，无论是激动剂，促进有效的T细胞反应，或者促进有效的T细胞反应，或拮抗剂，抑制t cel反应。我们将通过两个具体目标来实现这些目标。 1。在CD28的腔内结构域中产生结构突变，该突变要么以低自发形式锁定CD28，要么稳定高自发构象。 2。识别小分子激动剂和拮抗剂。