Sphingolipids in Cancer Biology and Therapy

癌症生物学和治疗中的鞘脂

基本信息

批准号：
9130745
负责人：
YUSUF AWNI HANNUN
金额：
$ 130.38万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130745
关键词：
ABL1 gene Address Advanced Development Aging Animal Model Animals Apoptosis Attenuated Basic Science Biology Cancer Biology Cancer Cell Growth Regulation Cells Cellular Membrane Cellular biology Ceramidase Ceramides Cessation of life Clinical Country Cyclic AMP Development Differentiation and Growth Discipline Down-Regulation Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Event Goals Human IL6 gene In Vitro Induction of Apoptosis Inflammation Knowledge Lead Legal patent Lipid Chemistry Lipids Malignant Neoplasms Measures Mediating Mediator of activation protein Medicine Metabolism Methodology Methods Molecular Molecular Probes Neoplasm Metastasis Pathway interactions Phase Principal Investigator Productivity Publications RANTES Regulation Research Research Personnel Resource Sharing Role SPHK1 enzyme Signal Pathway Signal Transduction Skin Skin Carcinoma Sphingolipids Sphingosine Synthesis Chemistry TP53 gene Technology Testing Therapeutic Translating Translational Research Translations Tumor Promotion Tumor Suppressor Proteins Work acid sphingomyelinase angiogenesis anticancer research base cancer cell cancer therapy carcinogenesis ceramide 1-phosphate chemokine cytokine frontier human disease in vivo Model inhibitor/antagonist insight keratinocyte lipid metabolism mutant neoplastic cell new therapeutic target novel novel marker novel therapeutics physical property pre-clinical preclinical study programs public health relevance receptor senescence sphingosine 1-phosphate tandem mass spectrometry therapeutic development tumor tumor initiation tumorigenesis tumorigenic working group

项目摘要

DESCRIPTION (provided by applicant): The overall organizing hypothesis of this Program posits that bioactive sphingolipids function as important regulators of several key tumor cell attributes, including tumor initiation, differentiation, growth, apoptosis, senescence, inflammation, invasion, and metastasis. As a corollary, enzymes of sphingolipid metabolism are emerging as specific and novel targets in modulating these important cancer attributes. Unfortunately, the study of bioactive lipids is rife with complications, both conceptual and technical and thus the study of lipids necessitates the collaborative interactions of various disciplines and specialized cores. Thus, we have evolved 4 distinct projects that collaborate to investigate the overall hypothesis: Project 1 will address the specific hypothesis that acid sphingomyelinase defines a novel pathway of cancer cell biology involving two specific mediators, the chemokine RANTES and the cytokine IL6, with important roles in cancer inflammation and metastasis. Project 2 will test the specific hypothesis that alkaline ceramidase 1 acts as a tumor suppressor in non-melanoma skin cancers and its downregulation promotes skin tumorigenesis by stimulating hyperproliferation of epidermal keratinocytes. Project 3 will test the hypothesis that loss of Sphingosine Kinase 1 is a key event in mediating the tumor suppressor effects of P53, especially on the induction of senescence. Project 4 will test the hypothesis that BCR-ABL1 transcriptionally regulates SMS1 and that elevated SMS1 activity sustains the tumorigenic potential of BCR-ABL1 positive cells. These 4 projects will be supported by two unique research cores: The Lipidomics Core which will provide analytical and synthetic lipid chemistry, and by a Sphingolipid Animal Cancer Pathobiology Core that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of in vivo carcinogenesis. This Program group has been highly integrated and productive and has advanced significantly our understanding of sphingolipids (one of the last frontiers of basic research) in caner biology and therapeutics. We are now poised to advance pre-clinical studies and translational research based on our understanding of these novel pathways. These studies continue to identify novel targets and strategies for cancer therapeutics.

描述（由申请人提供）：该计划的总体组织假设认为，生物活性鞘脂作为几种关键肿瘤细胞属性的重要调节剂，包括肿瘤起始，分化，生长，凋亡，衰老，炎症，炎症，入侵和转移。作为推论，鞘脂代谢的酶正在成为调节这些重要癌症属性的特定和新颖靶标。不幸的是，对生物活性脂质的研究充满了概念和技术的并发症，因此对脂质的研究需要各种学科和专业核心的协作相互作用。因此，我们发展了4个不同的项目，这些项目协作研究了总体假设：项目1将解决以下特定的假设：酸鞘磷脂酶定义了涉及两个特定介体的趋化因子rantes和细胞因子IL6的癌细胞生物学的新途径，在癌症炎症和转移中具有重要作用。项目2将检验以下特定假设，即碱性神经酶1在非黑色素瘤皮肤癌中充当肿瘤抑制剂，其下调通过刺激表皮角质形成细胞的高增殖来促进皮肤肿瘤发生。项目3将检验以下假设：鞘氨醇激酶1的丧失是介导p53肿瘤抑制作用的关键事件，尤其是在衰老诱导方面。项目4将测试BCR-ABL1转录调节SMS1的假设，而SMS1活性升高则维持BCR-ABL1阳性细胞的致瘤潜力。这4个项目将得到两个独特的研究核心：脂质组学核心将提供分析和合成脂质化学，以及鞘脂动物癌症病理学病理学核心核心，该核心核心侧重于突变体/敲击鞘脂代谢的酶和体内癌变模型的酶。该计划小组已经高度融合和富有成效，并在Caner Biology和Therapeatics中对鞘脂的理解（基础研究的最后一个领域之一）都显着提高了。现在，我们准备基于对这些新颖途径的理解来推进临床前研究和翻译研究。这些研究继续确定癌症治疗剂的新目标和策略。