Neutral Ceramidase in Colon Cancer

结肠癌中的中性神经酰胺酶

• 批准号: 8577881
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 33.88万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577881
• 关键词: Aberrant crypt foci; Address; Adenocarcinoma; Animals; Apoptosis; Attenuated; Azoxymethane; Benign; Biochemical; Biology; Cell Culture Techniques; Cell Cycle Regulation; Cells; Cellular Stress; Ceramidase; Ceramides; Cessation of life; Chemicals; Chemoprevention; Cloning; Collaborations; Colon; Colon Adenocarcinoma; Colon Carcinoma; Colorectal Cancer; Development; Down-Regulation; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exhibits; Genes; Growth; Human; Hydrolysis; Incidence; Induction of Apoptosis; Knock-out; Knockout Mice; Laboratories; Lead; Lipids; Malignant Neoplasms; Mediator of activation protein; Metabolism; Modeling; Molecular; Mus; Nature; Oncogenic; Pathogenesis; Pathway interactions; Play; Prevention; Property; Regulation; Regulatory Pathway; Resistance; Role; Sphingolipids; Sphingosine; Therapeutic; Treatment outcome; United States; base; biological adaptation to stress; cancer cell; cancer therapy; cell growth; chemotherapy; in vivo; inhibitor/antagonist; inorganic phosphate; intestinal epithelium; knock-down; lipid mediator; mouse model; novel; public health relevance; response; senescence; small molecule; sphingosine 1-phosphate; tumor; tumor progression

DESCRIPTION (provided by applicant): The long-term aims of this project are to understand the role of neutral ceramidase (nCDase) in colon cancer pathogenesis, chemoprevention, and therapeutics. nCDase is a key, yet poorly studied, enzyme in regulating the interconversion of important bioactive molecules that include ceramides with an overall anti- tumor properties and sphingosine 1-phosphate with tumor-promoting properties. Our laboratory first identified, purified, and cloned the mammalian nCDase and studied its biochemical properties. In recent studies, we find that nCDase is enriched in the intestinal epithelium, and ongoing preliminary results show dramatic effects of deletion of nCDase on development of colon cancer in a mouse model of AOM (azoxymethane)-induced colonic adenocarcinoma. Additional recent studies are beginning to implicate this enzyme in the ss-catenin pathway. Based on the above, we propose the hypothesis that that nCDase is a 'synthetically lethal' target for transformed colon cells, especially those defined by abnormal activation of the ss-catenin pathway. We will employ chemical, biochemical, molecular, and in vivo studies to evaluate this hypothesis and to advance nCDase as a novel target. We will focus on the following specific aims: 1) Establish and define the role of NCDase in regulating colon cancer progression, by a) defining the in vivo role of nCDase in the development of colon cancer using the knock out mouse; b) determine the expression of nCDase in human colon cancer; and c) define the in vivo and cellular roles of nCDase in regulating cell growth and stress responses in colon cancer. 2) Determine the mechanisms underlying the prevention of colon cancer progression by disruption of nCDase. We will focus on a) determining the role of nCDase in regulating the ss-catenin pathway of colon cancer development in vivo and in cell culture models; b) defining the candidate bioactive lipid mediators of action of nCDase and roles of downstream targets; and c) defining mechanisms by which nCDase regulates the ss-catenin pathway. 3) Develop NCDase as a novel target for cancer therapy. Here we will a) develop small molecule inhibitors of nCDase based on initial hits; b) evaluate these inhibitors for their ability to inhibit nCDase in cells and the functional consequences; c) develop PK/PD studies; and d) Define the effects of these inhibitors in vivo. These results may allow us to define and establish nCDase as a novel and heretofore unappreciated major regulator of colon cancer progression. nCDase may emerge as a novel and effective target for rationally-based chemotherapy.

描述（由申请人提供）：该项目的长期目的是了解中性神经酰胺酶（NCDase）在结肠癌发病机理，化学预防和治疗剂中的作用。 NCDase是一个关键，但研究的酶是调节重要生物活性分子的相互转化的酶，包括具有整体抗肿瘤特性的神经酰胺和具有肿瘤促进性质的1-磷酸鞘氨醇。我们的实验室首先确定，纯化和克隆了哺乳动物的NCDase，并研究了其生化特性。在最近的研究中，我们发现NCDase在肠上皮中富集，并且持续的初步结果表明，在AOM小鼠模型（二甲烷）诱导的结肠腺癌中，NCDase缺失对结肠癌发展的巨大影响。最近的其他研究开始牵涉到SS-catenin途径中的这种酶。基于上述，我们提出了以下假设：NCDase是转化的结肠细胞的“综合”靶标，尤其是由SS-catenin途径异常激活所定义的靶标。我们将采用化学，生化，分子和体内研究来评估这一假设并将NCDase推进为新靶标。我们将重点关注以下特定目的：1）通过a）使用敲除小鼠来确定NCDase在调节结肠癌进展中的作用并定义NCDase在调节结肠癌进展中的作用； b）确定NCDase在人结肠癌中的表达； c）定义NCDase在调节结肠癌细胞生长和胁迫反应中的体内和细胞作用。 2）确定通过破坏NCDase预防结肠癌进展的机制。我们将重点介绍a）确定NCDase在体内和细胞培养模型中结肠癌发展的SS-catenin途径中的作用； b）定义NCDase的作用的候选生物活性脂质介质以及下游靶标的作用； c）定义NCDase调节SS-catenin途径的机制。 3）开发NCDase作为癌症治疗的新靶标。在这里，我们将a）基于初始命中发展NCDase的小分子抑制剂； b）评估这些抑制剂的抑制能力和功能后果的能力； c）开发PK/PD研究； d）定义这些抑制剂在体内的作用。这些结果可能使我们能够将NCDase定义为结肠癌进展的新型和迄今为止未经批准的主要调节剂。 NCDase可能会成为基于理性化疗的新颖有效的靶标。