Molecular Determinants of Brain metastatic Melanoma

描述：(改编自调查员的摘要)负责的机制 恶性黑色素瘤进展为高度侵袭性脑转移 疾病在很大程度上仍是未知的。我们之前已经证明了某些 神经营养因子及其受体p75受体调控黑色素瘤侵袭的研究 细胞到大脑和一种叫做乙酰肝素酶的酶的活性。这 酶是成功降解该物质的关键决定因素 肿瘤周围细胞外基质(ECM)：肝素酶降解肝素 硫酸盐蛋白多糖(HSPG)，这是ECM的重要组成部分，在位点 在HS线性链内。我们的假设是NT/p75NTR起重要作用 在黑色素瘤脑侵袭中，NT调节的乙酰肝素酶在 转移性黑色素瘤进展是抗转移的潜在靶点 毒品。本应用程序目标是将p75NTR功能确定为 脑转移瘤形成的分子决定因素及乙酰肝素酶的作用 在侵袭和血管生成方面。我们选择了p75NTR低/高的黑色素瘤细胞 表达并产生了抗人乙酰肝素酶的单抗 抑制其酶活性和实验性转移形成。在……里面 此外，我们还获得了最近克隆的人类乙酰肝素酶，相关的 探针和新型重要的酶抑制剂。我们的具体目标是： 1.确定p75NTR为脑转移性黑色素瘤的分子决定因素 细胞，这将通过改变p75NTR基因的表达和 P75NTR突变体在裸鼠体内器官定植能力的分析， 尤其是对大脑来说。 2.表征NT调控的乙酰肝素酶基因在下列特定步骤中的表达 恶性黑色素瘤的转移，这将通过研究 人乙酰肝素酶的分布及其作用机制研究 乙酰肝素酶在黑色素瘤转移多步过程中的作用。 3.确定乙酰肝素酶在血管生成中的作用，这将是 通过将血管生成分子和模型与乙酰肝素酶联系起来实现的 使用纯化的酶和HS底物亚群的功能 来自相应的HSPG。 我们预计，我们提议的研究结果将从根本上 推进脑肿瘤生物学和转移性细胞外基质处理领域。的 具有重大意义，预计它们将提供新的预防和控制目标 治疗干预措施将对不断增长的 患有恶性黑色素瘤并正在经历 黑色素瘤问题的紧迫性。

DESCRIPTION: (Adapted from the investigator's abstract) Mechanisms responsible for malignant melanoma progression to highly aggressive brain-metastatic disease remain largely unknown. We have previously demonstrated that certain neurotrophins (NT) and their receptor p75 TR modulate the invasion of melanoma cells to the brain and the activity of an enzyme, called heparanase. This enzyme is a key determinant for the successful degradation of the tumor-surrounding extracellular matrix (ECM): heparanase degrades heparan sulfate proteoglycans (HSPGs), which are important ECM components, at sites within HS linear chains. Our hypothesis is that NT/p75NTR play important roles in melanoma brain invasion and that NT-regulated heparanase is critical in the metastatic melanoma progression being a potential target for antimetastasis drugs. The objective of this application is to determine p75NTR function as a molecular determinant of brain metastases formation and the role of heparanase in invasion and angiogenesis. We selected melanoma cells with low/high p75NTR expression and generated a monoclonal antibody against human heparanase that inhibits its enzymatic activity and experimental metastases formation. In addition, we have access to the recently cloned human heparanase, related probes, and novel important enzyme inhibitors. Our specific aims are: 1. To define p75NTR as a molecular determinant of brain-metastatic melanoma cells, which will be accomplished by modifying p75NTR gene expression and analysis of p75NTR variants for their organ colonizing abilities in nude mice, in particular to the brain. 2. To characterize NT-regulated heparanase gene expression at specific steps of metastasis in malignant melanoma, which will be accomplished by studying the distribution and mechanisms of human heparanase to test the precise function of heparanase in the multistep process of melanoma metastasis. 3. To determine the role of heparanase in angiogenesis, which will be accomplished by relating angiogenic molecules and models to heparanase functionality by using purified enzyme and HS substrates subpopulations from corresponding HSPGs. We anticipate that the results of our proposed research will fundamentally advance the field of brain tumors biology and metastatic ECM processing. Of significance, they are expected to provide new targets for preventive and therapeutic interventions that will be particularly important to the growing numbers of persons who have malignant melanoma, and are experiencing the "urgency" of the melanoma problem.