Establishing Apoptotic Thresholds: Insights from Neurons and Stem Cells to Cancer

建立细胞凋亡阈值：从神经元和干细胞对癌症的见解

基本信息

批准号：
9281085
负责人：
Mohanish P Deshmukh
金额：
$ 52.36万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2016-06-01 至 2021-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Despite the identification of the main components of the mammalian apoptotic pathway, the differences in the regulation of apoptosis in various primary cells remain surprisingly unexplored. Our unique ongoing contribution to the apoptosis field has been to define how different cell types set the apoptosis threshold to optimally matche their physiological functions and adapt to changing environments. Indeed, we believe that new paradigms of apoptosis regulation remain to be discovered in physiologically distinct cell types. Our lab has discovered that the apoptotic pathway is highly restricted in postmitotic cells such as neurons, cardiomyocytes, and myotubes, as compared to mitotic cells such as fibroblasts. While a strict regulation of apoptosis is critical for the long-term survival of postmitotic cells, mitotic cells need to maintain their ability to activate apoptosis rapidly as they can be at continual risk of becoming cancerous. Therefore, cells must efficiently balance the need for having a primed apoptotic pathway versus the risks associated with cell death. In fact, we have seen this best exemplified in embryonic stem (ES) cells which engage mechanisms that both prime the apoptotic pathway for rapid death in response to DNA damage, while also engaging cell survival mechanisms in response to mitochondrial damage. Thus, ES cells appear to have an exquisite capability to respond to the specific damage stimuli with mechanisms that ensure both genomic integrity and optimal survival. In this MIRA proposal, we wish to use both targeted and broad integrative approaches to examine the distinct mechanisms of apoptosis regulation and define their physiological importance in health and disease. Our focus is on the two extremes of the apoptosis control we identified: 1) Mechanisms that resistant apoptosis and promote survival after mitochondrial damage (e.g. our findings that the E3 ligase PARC mediates the degradation of cytosolic cytochrome c), and 2) Mechanisms that prime cells for rapid apoptosis (e.g. our discovery that Bax is maintained in an active state in stem cells). We will use primary neurons and human embryonic stem (hES) cells, conduct innovative screens and examine disease implications in models of cancer and neurodegeneration. In particular, we are excited that the MIRA opportunity would enable our ambitious plans to use the powerful capability of hES cells to define how the apoptotic machinery undergoes dynamic changes with cellular differentiation.

描述（由应用程序提供）：尽管鉴定出哺乳动物凋亡途径的主要成分，但各种主要细胞中凋亡调节的差异仍然令人惊讶。我们对凋亡领域的独特持续贡献是定义不同的细胞类型如何设置凋亡阈值以最佳匹配其物理功能并适应不断变化的环境。确实，我们认为，在物理上不同的细胞类型中，凋亡调节的新范例仍有待发现。我们的实验室发现，与有丝分裂细胞（如成纤维细胞）相比，在神经元，心肌细胞和肌管等后有丝分裂细胞（例如神经元，心肌细胞和肌管）中，凋亡途径受到高度限制。虽然严格调节细胞凋亡对于有丝分裂后细胞的长期存活至关重要，但有丝分裂细胞需要保持其迅速激活凋亡的能力，因为它们可能会持续被取消的风险。因此，细胞必须有效地平衡具有主要凋亡途径的需求与与细胞死亡有关的风险。实际上，我们已经看到了这种最佳的示例在胚胎茎（ES）细胞中，这些细胞既涉及源自DNA损伤的快速死亡的凋亡途径，同时还可以响应线粒体损伤而引起细胞存活机制。这样，ES细胞似乎具有针对特定损伤刺激的独特能力，其机制可确保基因组完整性和最佳生存。在此MIRA建议中，我们希望使用靶向和广泛的整合方法来检查凋亡调节的不同机制，并确定其在健康和疾病中的身体重要性。 Our focus is on the two extremes of the apoptosis control we identified: 1) Mechanisms that resistant apoptosis and promote survival after mitochondrial damage (e.g. our findings that the E3 ligase PARC mediates the degradation of cytosolic cytochrome c), and 2) Mechanisms that prime cells for rapid apoptosis (e.g. our discovery that Bax is maintained in an active state in stem cells).我们将使用原发性神经元和人类胚胎（HES）细胞，在癌症和神经变性模型中进行创新的筛查和检查疾病的影响。特别是，我们很兴奋的是，MIRA机会将使我们雄心勃勃的计划使用HES细胞的强大能力来定义凋亡机械如何通过细胞分化而动态变化。