PROTEOMIC ANALYSIS OF APOPTOTIC MECHANISMS IN CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 默里·约翰斯顿 肿瘤细胞凋亡机制的蛋白质组学分析 神经母细胞瘤是在婴儿中发现的主要实体瘤，是一种独特的儿童癌症。虽然早期发现的肿瘤通常会消退，但直到患者年龄较大(2岁以上)时才能发现这种疾病，疾病表现为3期或4期，患者的预后很差。这些患者通常会接受积极的手术、放射和化疗，试图根除癌症。然而，全身细胞毒化疗的副作用对儿童尤其严重，这些患者的治疗成功率仍然很低。显然，需要开发更好的治疗方法来治疗这种癌症。 我们提出了一个假设，即溶酶体蛋白水解酶是潜在的独特的治疗靶点，可以被抑制来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的抑制都通过诱导细胞凋亡而导致神经母细胞瘤细胞死亡。我们发现，诱导细胞凋亡是神经母细胞瘤细胞独有的，因此我们正在寻找这些蛋白水解酶的抑制剂，作为神经母细胞瘤动物模型的潜在治疗化合物(一项由Nemour支持的研究)。在目前的研究中，我们建议确定这种蛋白水解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，加上我们的转化性治疗研究，对于开发适合NIH R01资助的项目至关重要。我们还将利用这个项目开发新的蛋白质组技术，并预计这将带来更多的资金机会，并显著提高特拉华州的蛋白质组能力。

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.