Notch Regulation of Hematopoietic Cell Fates

造血细胞命运的Notch调控

基本信息

批准号：
10335128
负责人：
MARTHA S JORDAN
金额：
$ 45.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335128
关键词：
Adoptive Transfer Agonist Antibody Formation Antigens B-Lymphocytes Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Compartmentation Cell Differentiation process Cell physiology Cells Chronic Data Exhibits Exposure to Goals Hematopoietic Immune Immune response In Vitro Infection Interleukin-2 Knowledge Lead Lymphocytic choriomeningitis virus Malignant Neoplasms Mediating Molecular Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mus Nature Pathway interactions Phase Progressive Disease Proliferating Proteins Regulation Regulatory Pathway Research Resolution Role Signal Pathway Signal Transduction Structure T cell differentiation T cell response T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Intervention Viral adaptive immune response arm base chronic infection cytokine effector T cell exhaust exhaustion improved outcome in vivo insight notch protein novel novel therapeutic intervention protein degradation response therapeutic target transcription factor

项目摘要

T cells are pivotal players in the adaptive immune response. However, when continuously exposed to antigen, as in persistent infection or cancer, T cells lose effector function and ultimately become exhausted, leading to chronic infection or progressive disease. Recent therapeutic advances are based on reversing these natural mechanisms set in place to “quiet” activated T cells during the resolution phase of an immune response, and in doing so, reinvigorate immune responses crippled by T cell exhaustion. However, response rates remain low in many settings; thus, additional strategies are needed. Crucial for developing such strategies is to identify new targetable pathways, which is currently hampered by our limited basic knowledge of the negative regulatory pathways that inhibit T cell activation. We recently discovered that the pseudokinase Trib1 is a novel negative regulator of T cell activation, which is induced upon T cell receptor (TCR) stimulation. Our overall goal is to determine the cellular and molecular mechanisms by which Trib1 regulates T cell responses. Our preliminary data generated both in vitro and in vivo suggest that in the absence of Trib1, T cells are hyper-activated and are better able to control chronic infections. Mechanistically, Trib1 appears to exert its effects on T cells via a novel mechanism of regulating NF-κB. Based on these preliminary data, our overarching hypothesis is that Trib1 suppresses signaling pathways that promote T cell activation and promotes immune cell exhaustion by limiting T cell effector function and B cell help. This hypothesis will be tested in two aims: Aim 1 will define the cellular responses regulated by Trib1, and Aim 2 will determine the signaling pathways responsible for these findings. Our findings may lead to new insights into controlling T cell activation and exhaustion in multiple scenarios, including chronic infections and cancer, and in doing so, identify new avenues for therapeutic interventions.

T细胞是自适应免疫响应中的关键参与者。但是，当不断暴露于抗原，例如在持续感染或癌症中，T细胞失去了效应子功能，最终会筋疲力尽，导致慢性感染或进行性疾病。最近的治疗进步基于逆转这些自然机制，以“安静” 在免疫响应的分辨率阶段激活的T细胞，然后这样做，振兴的免疫反应因T细胞耗尽而瘫痪。但是，回复率仍然在许多情况下低；因此，需要其他策略。对于开发这种此类至关重要策略是确定新的目标途径，目前我们有限抑制T细胞激活的负调节途径的基本知识。我们最近发现，假子酶Trib1是T细胞的新型负调节剂激活是在T细胞受体（TCR）刺激上诱导的。我们的总体目标是确定Trib1调节T细胞反应的细胞和分子机制。我们的初步数据在体外和体内都产生细胞被过度激活，并且能够更好地控制慢性感染。机械上，部落1 似乎通过调节NF-κB的新机制对T细胞执行其影响。基于这些初步数据，我们的总体假设是Trib1抑制信号通路促进T细胞激活并通过限制T细胞效应器来促进免疫细胞耗尽功能和B细胞帮助。该假设将以两个目的进行检验：AIM 1将定义细胞由Trib1调节的响应和AIM 2将确定负责的信号通路这些发现。我们的发现可能会导致对控制T细胞激活的新见解和在多种情况下的疲惫，包括慢性感染和癌症，并这样做，确定治疗干预措施的新途径。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells.

DOI：
10.1371/journal.pone.0030656
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Pan X;Jones M;Jiang J;Zaprazna K;Yu D;Pear W;Maillard I;Atchison ML
通讯作者：
Atchison ML

The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development.

Notch2 介导的边缘区 B 细胞发育需要转录共激活因子 Maml1。

DOI：
10.1182/blood-2007-06-097030
发表时间：
2007
期刊：
Blood
影响因子：
20.3
作者：
Wu,Lizi;Maillard,Ivan;Nakamura,Makoto;Pear,WarrenS;Griffin,JamesD
通讯作者：
Griffin,JamesD

The Varied Roles of Notch in Cancer.

DOI：
10.1146/annurev-pathol-052016-100127
发表时间：
2017-01-24
期刊：
Annual review of pathology
影响因子：
0
作者：
Aster JC;Pear WS;Blacklow SC
通讯作者：
Blacklow SC

Notch signaling in mammalian hematopoietic stem cells.

DOI：
10.1038/leu.2011.127
发表时间：
2011-10
期刊：
Leukemia
影响因子：
11.4
作者：
Pajcini KV;Speck NA;Pear WS
通讯作者：
Pear WS

T cell factor 1 is required for group 2 innate lymphoid cell generation.

DOI：
10.1016/j.immuni.2012.12.003
发表时间：
2013-04-18
期刊：
Immunity
影响因子：
32.4
作者：
Yang Q;Monticelli LA;Saenz SA;Chi AW;Sonnenberg GF;Tang J;De Obaldia ME;Bailis W;Bryson JL;Toscano K;Huang J;Haczku A;Pear WS;Artis D;Bhandoola A
通讯作者：
Bhandoola A