Cleavage of Bcl-xL by Caspases contributes to cell death in vivo

Caspases 对 Bcl-xL 的裂解导致体内细胞死亡

基本信息

批准号：
9050122
负责人：
Jason Huska
金额：
$ 4.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050122
关键词：
Address Affect Affinity Age Aging Animals Apoptosis Apoptotic Architecture Atrophic Autoimmune Diseases BCL-2 Protein BCL2 gene Binding Body Weight decreased Bone Marrow CD8B1 gene Caspase Cell Death Cell Death Process Cells Cellularity Cessation of life Chimera organism Cleaved cell Communicable Diseases Cues Cytotoxic T-Lymphocytes Data Development Elderly Event Failure Family member Generations Goals Granzyme Immune response Immunity Influenza Knock-in Mouse Life Maintenance Malignant Neoplasms Mediating Mus Mutate Pattern Population Positioning Attribute Production Protein Family Proteins Resistance Role Signal Transduction Site Surface T cell response T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Thymocyte Selection Thymus Gland Transgenic Mice Tyrosine Virus aged base burden of illness cell killing cell mediated lymphocytolysis test immunosenescence in vivo influenzavirus inhibitor/antagonist insight killings knockin animal mortality mouse model neglect perforin prevent public health relevance response thymocyte

Address Affect Affinity Age Aging Animals Apoptosis Apoptotic Architecture Atrophic Autoimmune Diseases BCL-2 Protein BCL2 gene Binding Body Weight decreased Bone Marrow CD8B1 gene Caspase Cell Death Cell Death Process Cells Cellularity Cessation of life Chimera organism Cleaved cell Communicable Diseases Cues Cytotoxic T-Lymphocytes Data Development Elderly Event Failure Family member Generations Goals Granzyme Immune response Immunity Influenza Knock-in Mouse Life Maintenance Malignant Neoplasms Mediating Mus Mutate Pattern Population Positioning Attribute Production Protein Family Proteins Resistance Role Signal Transduction Site Surface T cell response T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Thymocyte Selection Thymus Gland Transgenic Mice Tyrosine Virus aged base burden of illness cell killing cell mediated lymphocytolysis test immunosenescence in vivo influenzavirus inhibitor/antagonist insight killings knockin animal mortality mouse model neglect perforin prevent public health relevance response thymocyte

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项目摘要

DESCRIPTION (provided by applicant): The goal for this project is to determine how cleavage of Bcl-xL by caspases contributes to cell death in vivo. Caspase cleavage of cellular substrates is a key event in mediating apoptosis. The Bcl-2 family member Bcl-xL is an inhibitor of apoptotic cell death, and can also be a substrate of caspases. Cleavage of Bcl-xL [not only abolishes its anti-death activity] but also convert Bcl-xL from a potent anti-apoptotic protein to potent pro-death molecule. Cells transfected with the N-terminally truncated Bcl-xL cleavage fragment (ΔN-Bcl-xL) display accelerated cell death. To probe the in vivo effects of Bcl-xL cleavage, a caspase-uncleavable Bcl-xL knock-in mouse was generated by mutating the two caspase cleavage sites within Bcl-xL. Interestingly, caspase-resistant Bcl-xL mice retain a healthy thymus in old age suggesting that cleavage of Bcl-xL leads to cell death that results in thymic atrophy. My preliminary data suggest that these mice may have defective positive selection (generation of a viable T-cell receptor). Therefore, we will explore the possibility that caspase-cleavage of Bcl-xL kills developing thymocytes that fail the positive selection checkpoint. By doing so, we will provide mechanistic insights into what is termed "death by neglect", the failure of thymocytes to receive survival cues. Because these mice maintain a morphologically normal thymus throughout life, I will determine if they also maintain normal immune responses to influenza virus. Influenza particularly affects the elderly, who display poor T-cell responses to the virus. This is presumed to be because of immunosenescence, in part attributed to thymic atrophy. A long-standing assumption is that thymic atrophy contributes to waning immune responses due to decreased T-cell production, but mouse models to definitively test this hypothesis have been lacking. Therefore, we are in a unique position to determine if preserved thymic function also confers protection from influenza infection in aged animals. We will critically evaluate whether thymic atrophy compromises the immune responses needed to control influenza. These studies will also address the role of thymic selection and T-cell contributions to influenza virus immunity.

描述（由适用提供）：该项目的目标是确定胱天蛋白酶对BCL-XL的裂解如何促进体内细胞死亡。细胞底物的caspase裂解是介导凋亡的关键事件。 Bcl-2家族成员BCl-XL是凋亡细胞死亡的抑制剂，也可以是caspase的底物。 Bcl-XL的裂解[不仅废除了其抗死活性]，而且还将BCl-XL从有效的抗凋亡蛋白转化为潜在的亲死亡分子。用N末端截断的Bcl-XL裂解片段（ΔN-BCl-XL）的N末端截断的细胞转化。为了探测Bcl-XL裂解的体内效应，通过突变Bcl-XL内的两个caspase裂解位点来产生caspase- caspase-bcl-xl敲入小鼠。有趣的是，caspase耐药的BCL-XL小鼠在老年中保留健康的胸腺，这表明Bcl-XL的裂解会导致细胞死亡，从而导致胸腺萎缩。我的初步数据表明，这些小鼠可能有缺陷的阳性选择（生成可行的T细胞受体）。因此，我们将探讨 BCL-XL的caspase裂解杀死了开发胸腺细胞，使阳性选择检查点失败。通过这样做，我们将提供机械见解，以了解所谓的“被忽视”，胸腺细胞未能获得生存线索的失败。由于这些小鼠一生都保持形态上正常的胸腺，因此我将确定它们是否还保持正常的免疫反应对病毒的影响。流感特别影响年龄较大的人，他们对病毒的T细胞反应不佳。这被认为是由于免疫，部分归因于胸腺萎缩。一个长期以来的假设是，胸腺萎缩会导致由于T细胞产生的减少而导致免疫血液的减弱，但是缺乏小鼠模型来检验该假设。因此，我们处于独特的位置，可以确定保留的胸腺功能是否也赋予了影响诱导动物的保护。我们将批判性地评估胸腺萎缩是否会损害控制影响所需的免疫回报。这些研究还将解决胸腺选择和T细胞对影响ZA病毒免疫的作用。