Drug Delivery at the Immunological Synapse

免疫突触的药物输送

• 批准号: BB/I013407/2
• 负责人: Daniel Davis
• 金额: $ 32.6万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI013407%2F2
• 关键词: Drug; Delivery; Immunological; Synapse

We have given names to nearly all the different protein molecules that mediate communication between human cells. Now, the audacious goal of contemporary cell biology is to understand how the billion proteins in an average cell allow them to move, multiply, create a brain or defend us against viruses and bacteria. Imaging where and when proteins interact with each other has a major role to play at this frontier. Recent imaging of just a few types of proteins has already led to important new concepts in how immune cells communicate with each other and how they recognize signs of disease. Images of immune cells contacting other cells have revealed temporary membrane structures, often called immune synapses, similar to the synapses that nerve cells make with one another for communication. It has been postulated that one function for such an immune synapse is to assemble a 'gasket' that to some extent isolates the synaptic cleft from the bulk extracellular environment. However, the precise extent as to which the synapse acts as a gasket has not been studied. This fundamental knowledge can have a major importance for the design of novel drugs, because understanding to what extent and how the immune synapse is shielded from the bulk extracellular environment could, in the longer term, facilitate the rational design of drugs that penetrate the immune synapse to work more effectively, e.g. for blocking proteins secreted across the synapse. It may also be useful to note that to realize the proposed experiments we will exploit new imaging technologies which will be of broad interest across several biological research fields. Patents may be sought upon development of specific applications. In addition to the specific hypotheses to be studied here, the application of high-resolution microscopy to study immune cell interactions is also to some extent explorative and hypothesis-forming; this is still a very young field and more surprises are surely in store.

我们已经给几乎所有不同的蛋白质分子命名，这些蛋白质分子介导人类细胞之间的通讯。现在，当代细胞生物学的大胆目标是了解平均细胞中的十亿蛋白质如何使它们移动，繁殖，创造大脑或保护我们免受病毒和细菌的侵害。成像蛋白质在何处以及何时相互作用在这一前沿领域发挥着重要作用。最近对几种蛋白质的成像已经在免疫细胞如何相互交流以及它们如何识别疾病迹象方面产生了重要的新概念。免疫细胞与其他细胞接触的图像揭示了临时的膜结构，通常称为免疫突触，类似于神经细胞相互通信的突触。据推测，这种免疫突触的一个功能是组装一个“垫圈”，在某种程度上将突触间隙与大量的细胞外环境隔离。然而，突触作为垫圈的精确程度还没有被研究过。这一基础知识对于新药的设计非常重要，因为从长远来看，了解免疫突触在多大程度上以及如何与大量细胞外环境隔离，可以促进合理设计穿透免疫突触的药物，以更有效地发挥作用，例如阻断突触分泌的蛋白质。值得注意的是，为了实现所提出的实验，我们将利用新的成像技术，这将在几个生物研究领域引起广泛兴趣。在开发具体应用时可申请专利。除了这里要研究的特定假设之外，高分辨率显微镜在研究免疫细胞相互作用方面的应用在某种程度上也是探索性的和假设性的;这仍然是一个非常年轻的领域，肯定会有更多的惊喜。

项目成果

Presenting the marvels of immunity.

展现免疫力的奇迹。

• DOI: 10.1038/nri3681
• 发表时间: 2014
• 期刊: Nature reviews. Immunology
• 作者: Davis DM

3-D stimulated emission depletion microscopy with programmable aberration correction

• DOI: 10.1002/jbio.201300041
• 发表时间: 2014-01-01
• 期刊: JOURNAL OF BIOPHOTONICS
• 影响因子: 2.8
• 作者: Lenz, Martin O.;Sinclair, Hugo G.;French, Paul M. W.
• 通讯作者: French, Paul M. W.

The immune synapse clears and excludes molecules above a size threshold.

• DOI: 10.1038/ncomms6479
• 发表时间: 2014-11-19
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cartwright, Adam N. R.;Griggs, Jeremy;Davis, Daniel M.
• 通讯作者: Davis, Daniel M.

Nanoscale ligand spacing influences receptor triggering in T cells and NK cells.

• DOI: 10.1021/nl403252x
• 发表时间: 2013
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Delcassian D;Depoil D;Rudnicka D;Liu M;Davis DM;Dustin ML;Dunlop IE
• 通讯作者: Dunlop IE

A peptide antagonist disrupts NK cell inhibitory synapse formation.

• DOI: 10.4049/jimmunol.1201032
• 发表时间: 2013-03-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Borhis G;Ahmed PS;Mbiribindi B;Naiyer MM;Davis DM;Purbhoo MA;Khakoo SI
• 通讯作者: Khakoo SI