A QUANT PROTEOMICS APPR TO UNDERSTANDING THE SIGMA-1 RECEPTOR SIGNALING PATHW

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 σ受体在肿瘤和各种组织来源的肿瘤细胞系中的过表达是有据可查的，并且强调了σ受体在癌症的病理生理学中的假定的重要作用。具体地，关于σ-1受体，其在细胞中的瞬时过表达部分地保护免于凋亡刺激，而受体的基因沉默导致乳腺细胞系增殖的统计学显著降低。尽管还没有鉴定出σ受体的内源性配体，但使用小分子激动剂激活σ-1受体似乎进一步扩展了其“凋亡抗性”能力。更有趣的是，σ-1受体的拮抗作用逆转了这种效应，导致肿瘤细胞由于程序性细胞死亡而丢失。显然，sigma-1受体是一种令人兴奋的新的潜在癌症诊断生物标志物，也是治疗干预的重要靶点。我们的目标是定义sigma-1受体如何介导其对细胞生存信号的控制;由于其结合胆固醇和调节脂筏的脂质组成的能力，我们假设sigma-1受体使用相互作用的蛋白质网络通过脂筏依赖性途径将配体结合事件转化为生物学作用。因此，我们计划通过追求一个特定的目标来实现该试点项目的目标：使用蛋白质组学技术以sigma-1受体信号传导依赖的方式识别调节其与脂筏关联的蛋白质。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over-expression of sigma receptors in tumors and in tumor cell lines of various tissue origins is well documented and underscores the putative essential role of sigma receptors in the pathophysiology of cancer. In regards to the sigma-1 receptor specifically, its transient overexpression in cells is partially protective against apoptotic stimuli while gene silencing of the receptor leads to a statistically significant decrease in proliferation of breast cell lines. Even though endogenous ligands for the sigma receptors have not yet been identified, activation of sigma-1 receptors using small molecule agonists appears to further extend its "apoptosis resistance" abilities. More interesting, antagonism of the sigma-1 receptor reverses this effect causing tumor cell loss due to programmed cell death. Clearly, the sigma-1 receptor is an exciting new potential biomarkers for cancer diagnosis and is also an important target for therapeutic intervention. Our objective is to define how the sigma-1 receptor mediates its control over cellular survival signals; and due to its ability to bind cholesterol and modulate the lipid composition of lipid rafts, we hypothesize that the sigma-1 receptor uses a network of interacting proteins to translate ligand binding events into biological action via a lipid-raft dependent pathway. Therefore, we plan to accomplish the objective of this pilot project by pursuing one specific aim: Identify proteins that modulate their association with lipid-rafts in a sigma-1 receptor signaling-dependent manner using proteomic technology.