PROTEOMIC ANALYSIS OF APOPTOTIC MECHANISMS IN CANCER

这个子项目是许多研究子项目中的一个 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， 因此可以在其他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。 默里约翰斯顿 肿瘤细胞凋亡机制的蛋白质组学研究 神经母细胞瘤是婴儿中发现的主要实体肿瘤，是儿童特有的癌症。 虽然早期检测到的肿瘤通常会消退，但该疾病通常直到患者年龄较大（超过2岁）才被检测到，并且该疾病呈现为3或4期，并且患者的预后很差。 这些患者通常接受积极的手术，放疗和化疗以试图根除癌症。 然而，一般的细胞毒性化疗的副作用是特别严重的儿童，这些患者的治疗成功率仍然很低。 显然，需要开发更好的疗法来治疗这种癌症。 我们已经提出了一个假设，即溶酶体蛋白酶是潜在的独特的治疗靶点，可以被抑制以调节神经母细胞瘤的进展，副作用有限。 我们发现，组织蛋白酶B和L的抑制通过诱导凋亡导致神经母细胞瘤细胞死亡。 我们发现细胞凋亡的诱导是神经母细胞瘤细胞所独有的，因此正在神经母细胞瘤动物模型中寻求这些蛋白酶的抑制剂作为潜在的治疗化合物（由Nemours支持的研究）。 在本研究中，我们建议确定这种蛋白酶抑制导致神经母细胞瘤细胞选择性凋亡的机制。 这些机制研究，加上我们的转化治疗研究，对于开发适合NIH R 01资助的项目至关重要。 我们还将利用该项目开发新的蛋白质组学技术，并预计这将导致额外的资金机会，并显着提高蛋白质组学能力在特拉华州。

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. Murray Johnston Proteomic Analysis of Apoptotic Mechanisms in Cancer Neuroblastoma is the major solid tumor found in infants and is a unique cancer of children. Although tumors that are detected early often regress, the disease is often not detected until the patient is older (above 2 years), and the disease presents as stage 3 or 4 and the prognosis for the patient is poor. These patients are typically treated with aggressive surgery, radiation and chemotherapy in attempts to eradicate the cancer. However, side effects of general cytotoxic chemotherapy are particularly severe for children, and the success rate for treatment of these patients remains poor. Clearly better therapies need to be developed to treat this cancer. We have developed a hypothesis that lysosomal proteases are potentially unique therapeutic targets that can be inhibited to regulate progression of neuroblastoma with limited side effects. We found that inhibition of both cathepsins B and L results in death of neuroblastoma cells by inducing apoptosis. We discovered that the induction of apoptosis is unique to neuroblastoma cells and consequently are pursuing inhibitors of these proteases as potential therapeutic compounds in an animal model of neuroblastoma (a study supported by Nemours). In the present study we propose to determine the mechanism by which this protease inhibition causes selective apoptosis of neuroblastoma cells. These mechanistic studies, coupled with our translational therapeutic studies, are essential to development of a project suitable for NIH R01 funding. We will also use this project to develop novel proteomic technologies and anticipate that this will lead to additional funding opportunities and significantly enhance proteomic capabilities in the State of Delaware.