权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of T cell inhibitory pathways

T细胞抑制途径的机制

基本信息

批准号：
8279467
负责人：
MANISH J BUTTE
金额：
$ 13.28万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-27 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279467
关键词：
Accounting Affect Agonist Antibodies Antigen-Presenting Cells Area Attenuated Autoimmune Diabetes Autoimmune Process Autoimmune Responses Autoimmunity Award Basic Science Binding CD28 gene CD80 gene CD8B1 gene Calcium Cells Cellular biology Cessation of life Chronic Clinical Medicine Communicable Diseases Complement Cytoskeleton Diabetes Mellitus Diabetes prevention Equilibrium Event Family Family member Genes Goals Hematopoietic Human Imagery Immune Immune system Immunity Immunoprecipitation Infection Knowledge Learning Ligands Ligation Mediating Mediator of activation protein Mentors Microscopy Modeling Molecular Mus Pathogenesis Pathway interactions Phosphotransferases Physicians Play Research Personnel Role Scientist Self Tolerance Self-control as a personality trait Signal Pathway Signal Transduction Synapses T cell regulation T cell response T-Cell Activation T-Lymphocyte Tail Techniques Testing Therapeutic Tumor Immunity career cell type clinically relevant immunological synapse in vivo insight medical schools microbial mutant prevent programs receptor response skills therapeutic target tool trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): The main goal of this K08 Award is to study a new T cell inhibitory pathway in the B7:CD28 family of costimulatory molecules that regulates T cell activation and tolerance. The PI will be mentored at Harvard Medical School by Dr. Arlene Sharpe, an expert in the area of T cell costimulation. We have found that Programmed Death-1 Ligand 1 (PD-L1) on T cells can interact with B7-1, and that this interaction can inhibit T cell responses. We will test the hypothesis that PD-L1 on T cells plays an important role in controlling T cell activation, effector responses, and autoimmunity. We have a number of unique tools, including gene-deficient mice and PD-L1 antibodies that enable us to dissect the molecular mechanisms of PD-L1 signaling on T cells and investigate its roles in controlling in vivo responses. Our specific aims are: 1. Establish the mechanisms by which PD-L1 on T cells exerts inhibitory effects in mice and humans. In this Aim, we will test whether PD-L1 on T cells exerts an inhibitory effect by 1) modifying TCR signaling pathways, and/or by 2) utilizing a signaling partner or second chain to enact inhibitory effects. We will also test if ligation of PD-L1 on human T cells is inhibitory. These subaims will provide insight into the mechanisms by which PD-L1 on T cells inhibits responses and the potential for therapeutic manipulation of PD-L1 on human T cells. 2. Determine the roles of PD-L1 on T cells and its partners at the immunological synapse (IS). T cells are activated and regulated by contact with APCs at the IS. B7-1 on APCs can interact with CD28, CTLA-4, or PD-L1 on the T cell, raising the question: how does PD-L1 compete with CD28 and CTLA-4 for B7-1 interactions? We will focus on how PD-L1 on T cells competes with CD28 for binding to B7-1 in the early synapse (microclusters) and the late synapse (T cell-DC synapse). These studies will complement those in Aim 1 to investigate another means by which PD-L1 on T cells may exert its inhibitory effects. 3. Characterize in vivo effects of PD-L1 on T cells: activation and autoimmunity. I will examine the in vivo role of PD-L1 on CD4 and CD8 T cells during activation and effector responses. This aim will test the hypothesis that the PD-L1 pathway may control self-reactive T cells during autoimmune responses in vivo, using an autoimmune model of diabetes. In this proposal, I plan to acquire new skills in areas of T cell biology, including microscopy and in vivo studies of autoimmunity. My long-term goal is to combine my background in basic science and clinical medicine to be an academic physician-scientist and independent investigator, examining the fundamental roles of inhibitory T cell pathways as they regulate autoimmunity and infectious diseases. RELEVANCE: Blockade of PD-L1 has become an important therapeutic target. These studies will provide insights into new mechanisms to control T cell responses in microbial immunity, tumor immunity, and autoimmunity, and will provide fundamental insights into mechanisms of inhibition of T cells.

描述（由申请人提供）：该K 08奖的主要目标是研究B7：CD 28共刺激分子家族中调节T细胞活化和耐受的新T细胞抑制途径。PI将在哈佛医学院接受T细胞共刺激领域专家Arlene Sharpe博士的指导。我们发现T细胞上的程序性死亡-1配体1（PD-L1）可以与B7-1相互作用，并且这种相互作用可以抑制T细胞反应。我们将检验T细胞上的PD-L1在控制T细胞活化、效应子应答和自身免疫中起重要作用的假设。我们有许多独特的工具，包括基因缺陷小鼠和PD-L1抗体，使我们能够剖析T细胞上PD-L1信号传导的分子机制，并研究其在控制体内反应中的作用。我们的具体目标是：1.建立PD-L1对T细胞在小鼠和人类中发挥抑制作用的机制。在此目的中，我们将测试T细胞上的PD-L1是否通过1）修饰TCR信号传导途径和/或2）利用信号传导伴侣或第二链产生抑制作用来发挥抑制作用。我们还将测试PD-L1在人T细胞上的连接是否具有抑制性。这些子目标将深入了解T细胞上的PD-L1抑制反应的机制以及PD-L1在人类T细胞上的治疗操作潜力。2.确定PD-L1对T细胞及其在免疫突触（IS）中的伙伴的作用。T细胞通过与IS处的APC接触而被激活和调节。APC上的B7-1可以与T细胞上的CD 28、CTLA-4或PD-L1相互作用，这就提出了一个问题：PD-L1如何与CD 28和CTLA-4竞争B7-1相互作用？我们将重点关注T细胞上的PD-L1如何与CD 28竞争结合早期突触（微簇）和晚期突触（T细胞-DC突触）中的B7-1。这些研究将补充目标1中的研究，以研究T细胞上PD-L1可能发挥其抑制作用的另一种方法。3.表征PD-L1对T细胞的体内作用：活化和自身免疫。我将研究PD-L1在活化和效应反应期间对CD 4和CD 8 T细胞的体内作用。该目的将使用糖尿病的自身免疫模型来检验PD-L1通路可以在体内自身免疫应答期间控制自身反应性T细胞的假设。在这个提议中，我计划获得T细胞生物学领域的新技能，包括显微镜和自身免疫的体内研究。我的长期目标是将我在基础科学和临床医学方面的背景联合收割机结合起来，成为一名学术医生-科学家和独立研究者，研究抑制性T细胞通路在调节自身免疫和传染病时的基本作用。相关性：PD-L1阻断已成为重要的治疗靶点。这些研究将为控制微生物免疫、肿瘤免疫和自身免疫中T细胞应答的新机制提供见解，并将为T细胞抑制机制提供基本见解。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single molecule labeling of an atomic force microscope cantilever tip.

原子力显微镜悬臂尖端的单分子标记。

DOI：
10.1063/1.4760283
发表时间：
2012
期刊：
Applied physics letters
影响因子：
4
作者：
Liu,Jianwei;Butte,ManishJ
通讯作者：
Butte,ManishJ

Customized atomic force microscopy probe by focused-ion-beam-assisted tip transfer.

通过聚焦离子束辅助尖端转移定制原子力显微镜探针。

DOI：
10.1063/1.4892075
发表时间：
2014
期刊：
Applied physics letters
影响因子：
4
作者：
Wang,Andrew;Butte,ManishJ
通讯作者：
Butte,ManishJ

Compound heterozygous mutation of Rag1 leading to Omenn syndrome.

DOI：
10.1371/journal.pone.0121489
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Matthews AG;Briggs CE;Yamanaka K;Small TN;Mooster JL;Bonilla FA;Oettinger MA;Butte MJ
通讯作者：
Butte MJ

Fast Stiffness Mapping of Cells Using High-Bandwidth Atomic Force Microscopy.

DOI：
10.1021/acsnano.5b03959
发表时间：
2016-01-26
期刊：
ACS nano
影响因子：
17.1
作者：
Wang A;Vijayraghavan K;Solgaard O;Butte MJ
通讯作者：
Butte MJ

Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications.

聚乙烯吡咯烷酮微针能够输送完整的蛋白质，用于诊断和治疗应用。

DOI：
10.1016/j.actbio.2013.04.045
发表时间：
2013
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Sun,Wenchao;Araci,Zeynep;Inayathullah,Mohammed;Manickam,Sathish;Zhang,Xuexiang;Bruce,MarcA;Marinkovich,MPeter;Lane,AlfredT;Milla,Carlos;Rajadas,Jayakumar;Butte,ManishJ
通讯作者：
Butte,ManishJ