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A novel melanoma therapeutic target: Elucidating the structure and mapping functional domains of the lncRNA SAMMSON

一种新的黑色素瘤治疗靶点：阐明 lncRNA SAMMSON 的结构和绘制功能域

基本信息

批准号：
9610860
负责人：
Aaztli Coria
金额：
$ 3.45万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9610860
关键词：
Adopted Androgens Apoptosis Architecture Binding Proteins Biological Assay Cell Line Cell Survival Cell physiology Cells Cellular Assay Cessation of life Chemicals Data Detection Diagnosis Elements Epidemic Exhibits Flow Cytometry Goals Health Human In Vitro Incidence Knowledge Learning Maintenance Malignant Neoplasms Maps Mediating Melanoma Cell Metastatic Melanoma Methods Mind Mitochondria Mitochondrial Proteins Modeling Nucleotides Oncogenic Oxidative Phosphorylation Pharmaceutical Preparations Population Protein Region Proteins RNA RNA-Protein Interaction Ribonuclease H Structural Models Structure Technology Therapeutic Tissue Sample Transcript Transcriptional Regulation Untranslated RNA base cancer therapy cellular protein p32 design epigenetic regulation in vitro Model in vivo inhibitor/antagonist melanoma novel steroid receptor RNA activator targeted treatment therapeutic target

项目摘要

A novel melanoma therapeutic target: Elucidating the structure and mapping functional domains of the lncRNA SAMMSON The incidence of melanoma has doubled since the 1970’s, thus, there is an urgent need for a cure for this cancer. SAMMSON (survival associated mitochondrial melanoma-specific oncogenic noncoding) is a long- noncoding RNA (lncRNA) expressed exclusively in malignant melanoma cells. In melanoma cells, depletion of SAMMSON induces apoptosis. This phenomenon suggests that SAMMSON is essential for melanoma cell survival, making SAMMSON an attractive target for anti-cancer therapy. SAMMSON interacts with p32, a protein necessary for mitochondrial maintenance; little else known about SAMMSON structure and function. To pursue a potential therapy targeting SAMMSON, it is necessary to determine the secondary structural ensembles that SAMMSON adopts in vivo and the SAMMSON structural requirements for interaction with p32. Although lncRNAs are implicated in a multitude of cellular processes, only a few lncRNA structures are known. Among those structures, specific domains have been found to be essential for lncRNA function. Thus, we propose to perform the following studies: (1) We will model the in vitro and in vivo secondary structures of SAMMSON using SHAPE-MaP, a high throughput RNA chemical probing technology, and (2) We will identify the domains within SAMMSON necessary for SAMMSON:p32 interaction. Completion of these Aims will provide crucial information necessary to design inhibitors of SAMMSON:p32 interaction that may be effective anti-melanoma agents.

一种新的黑色素瘤治疗靶点：阐明黑色素瘤的结构和定位功能域 lncRNA SAMMSON 自20世纪70年代以来，黑色素瘤的发病率翻了一番，因此，迫切需要治愈这种疾病癌SAMMSON（生存相关线粒体黑色素瘤特异性致癌非编码）是一个长期的，非编码RNA（lncRNA）仅在恶性黑素瘤细胞中表达。在黑素瘤细胞中， SAMMSON诱导细胞凋亡。这一现象表明，SAMMSON是黑色素瘤细胞所必需的。这使得SAMMSON成为抗癌治疗的有吸引力的靶点。SAMMSON与p32相互作用，线粒体维持所必需的蛋白质;对SAMMSON的结构和功能知之甚少。到为了寻求针对SAMMSON的潜在治疗，有必要确定其二级结构，集合，SAMMSON采用在体内和SAMMSON的结构要求与p32的相互作用。虽然lncRNA参与了许多细胞过程，但只有少数lncRNA结构是已知的。在这些结构中，已经发现特定结构域对于lncRNA功能是必需的。因此我们本文拟进行以下研究：（1）建立体外和体内的二级结构模型， SAMMSON使用SHAPE-MaP，一种高通量RNA化学探针技术，和（2）我们将鉴定 SAMMSON内SAMMSON：p32相互作用所必需的结构域。完成这些目标将提供设计SAMMSON：p32相互作用抑制剂所需的关键信息，抗黑素瘤剂。