Molecular Mechanisms of Apoptosis Regulation Through IP3 Receptors

IP3受体调控细胞凋亡的分子机制

• 批准号: 10202508
• 负责人: Navid Paknejad
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202508
• 关键词: Adopted; Apoptosis; Apoptotic; Autophagocytosis; BCL-2 Protein; BCL2 gene; Bad protein; Binding; Binding Sites; Bioenergetics; Cell Death; Cell Survival; Cell division; Cell physiology; Cells; Chronic Lymphocytic Leukemia; Complex; Cryoelectron Microscopy; Dependence; Electrophysiology (science); Enzymes; Follicular Lymphoma; Goals; Human; ITPR1 gene; Image; In Vitro; Inositol; Kinetics; Ligands; MCL1 gene; Malignant neoplasm of ovary; Mediating; Membrane; Mitochondria; Molecular; Molecular Conformation; Multiple Myeloma; Necrosis; Permeability; Physiological; Process; Publishing; Regulation; Resistance; Resolution; Role; Signal Transduction; Site; Stimulus; Structure; Testing; Therapeutic; Therapeutic Intervention; Titrations; Trefoil; Up-Regulation; Work; cancer cell; design; in vivo Model; large cell Diffuse non-Hodgkin' s lymphoma; lung small cell carcinoma; migration; mutant; nanomolar; neoplastic cell; particle; prevent; receptor; response; targeted treatment

Project Summary/Abstract Inositol 1,4,5-trisphosphate receptors (IP3Rs) are the primary intracellular Ca2+ release channels in non- excitable cells. IP3R activity drives numerous cellular processes including cell division, migration, mitochondrial bioenergetics, autophagy, apoptosis and necrosis. Due to its diverse roles in cell fate decisions, it is perhaps unsurprising that tumor cells can gain a selective advantage by co-opting and modifying the IP3R-mediated Ca2+ signaling networks that underlie these processes. One mechanism that cells use to escape programmed cell death is to increase expression of anti-apoptotic BCL2 proteins, including Bcl-2, Bcl-xL, and Mcl-1. Among their various anti-apoptotic roles in cells, BCL2 proteins bind to IP3R and modulate Ca2+ dynamics. Despite extensive characterization of the role of IP3R in apoptosis and the anti-apoptotic effects of BCL2-IP3R interactions, mechanistic understanding of IP3R gating and modulation by BCL2 proteins is poorly understood at the molecular level. It is clear, however, that BCL2-IP3R interactions promote cell survival in response to apoptotic insult. Interactions between BCL2 and IP3R throttle the cell between enhanced mitochondrial bioenergetics through activation of Ca2+-dependent enzymes and metabolites, and cell death through large Ca2+ flux into the mitochondrial, leading to mitochondrial Ca2+ overload and outer membrane permeabilization, the commitment step in apoptosis. In the proposed work, functional and structural approaches will be employed to establish a mechanistic understanding of activation of IP3R by Ca2+ and IP3, and inhibition of IP3R by high Ca2+ concentrations. Furthermore, through single channel studies and solution of a BCL2-IP3R complex structure, a mechanistic basis for the regulation of IP3R by BCL2 proteins will be developed. The work will provide a new framework by which we can understand IP3R-mediated cell death, paving the way for new understanding and the design of therapeutics.

项目概要/摘要 肌醇 1,4,5-三磷酸受体 (IP3R) 是非细胞内主要的细胞内 Ca2+ 释放通道。 兴奋细胞。 IP3R 活性驱动许多细胞过程，包括细胞分裂、迁移、线粒体 生物能学、自噬、细胞凋亡和坏死。由于其在细胞命运决定中的不同作用，它可能是 毫不奇怪，肿瘤细胞可以通过选择和修改 IP3R 介导的基因来获得选择性优势。 Ca2+ 信号网络是这些过程的基础。细胞用来逃避编程的一种机制 细胞死亡是为了增加抗凋亡BCL2蛋白的表达，包括Bcl-2、Bcl-xL和Mcl-1。之中 BCL2 蛋白在细胞中具有多种抗凋亡作用，可与 IP3R 结合并调节 Ca2+ 动力学。尽管 IP3R 在细胞凋亡中的作用以及 BCL2-IP3R 的抗细胞凋亡作用的广泛表征 对 IP3R 门控和 BCL2 蛋白调节的相互作用、机制了解甚少 在分子水平上。然而，很明显，BCL2-IP3R 相互作用可促进细胞存活 细胞凋亡的侮辱。 BCL2 和 IP3R 之间的相互作用抑制增强线粒体之间的细胞 通过激活 Ca2+ 依赖性酶和代谢物来实现生物能学，并通过大量的细胞死亡来实现生物能学。 Ca2+ 流入线粒体，导致线粒体 Ca2+ 超载和外膜透化， 细胞凋亡的承诺步骤。在拟议的工作中，功能和结构方法将 用于建立对 Ca2+ 和 IP3 激活 IP3R 以及抑制 IP3R 的机制的理解 高 Ca2+ 浓度。此外，通过单通道研究和 BCL2-IP3R 解决方案 复杂的结构，将开发 BCL2 蛋白调节 IP3R 的机制基础。工作 将提供一个新的框架，通过它我们可以理解IP3R介导的细胞死亡，为新的研究铺平道路 治疗方法的理解和设计。