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Investigating positionally conserved long non-coding RNA functions during melanocyte development in zebrafish and human melanoma.

研究斑马鱼和人类黑色素瘤黑色素细胞发育过程中位置保守的长非编码 RNA 功能。

基本信息

批准号：
2445510
负责人：
金额：
--
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2445510
关键词：
Investigating positionally conserved long non

项目摘要

Long non-coding RNAs (lncRNAs) have important regulatory roles within the genome with many lncRNAs found to be dysregulated during human disease. LncRNAs are a class of non-coding genes that do not code for proteins and are longer than 200bp in length. It is hypothesised that lncRNAs will play a vital regulatory role in neural crest differentiation, melanocyte development and consequently, human melanoma. The aim of this research project is to identify and characterise the function of positionally conserved lncRNAs regulated by MITF-SOX10 between human and zebrafish genomes during neural crest differentiation, melanocyte development and human melanoma.Melanoma is an aggressive skin cancer which derives from the malignant transformation of a type of skin cell called melanocytes and is associated with a poor prognosis once metastasised. Switching phenotypes to a de-differentiated neural crest stem cell-like state is hypothesised to contribute to therapeutic resistance observed in melanoma. During development, neural crest cells give rise to several types of cells including melanocytes. Highlighting the need for further understanding of the molecular mechanisms which govern the progression of melanoma as well as their associated developmental programmes to provide new therapeutic targets and improved prognosis. Research will focus on identifying positionally conserved MITF-SOX10 regulated lncRNAs in human (Homo sapiens) and zebrafish (Danio rerio) genomes (Objective 1). MITF and SOX10 are two transcription factors that regulate gene expression programmes involved in neural crest differentiation, development of melanocytes and human melanoma. This is an imperative initial step which will provide novel insights into the molecular mechanisms governing gene expression programmes during development and oncogenic events in melanoma, providing candidate lncRNAs to prioritise for further research. To ascertain the function of candidate lncRNAs during neural crest differentiation and melanocyte development, expression of lncRNAs will be attenuated in zebrafish as an in-vivo model (Objective 2). The use of a relevant in-vivo model will allow for the identification of lncRNAs important for neural crest differentiation and melanocyte development at different developmental stages. Through these experiments, molecular function of different lncRNAs can be assessed and characterised. Finally, to ascertain whether candidate lncRNAs identified are clinically relevant in human health, lncRNA expression be attenuated in-vitro in human melanoma cell lines (Objective 3). Through this objective, the impact of lncRNAs in human health in the context of melanoma can be assessed. Providing new therapeutic targets and biomarkers that can be used to improve melanoma therapeutics. The outcomes of these objectives will better our understanding of the function of lncRNAs and the molecular mechanisms that they govern to influence gene expression programmes for neural crest differentiation, melanocyte development and melanoma. This proposed work embodies one of BBSRC's priority areas: 'Bioscience for an Integrated Understanding of Health'.

长链非编码RNA（lncRNA）在基因组中具有重要的调节作用，许多lncRNA在人类疾病期间被发现失调。lncRNA是一类不编码蛋白质的非编码基因，长度超过200 bp。据推测，lncRNA将在神经嵴分化，黑素细胞发育以及因此的人黑色素瘤中发挥重要的调节作用。本研究的目的是鉴定和阐明在神经嵴分化、黑素细胞发育和人类黑色素瘤过程中，人类和斑马鱼基因组中由MITF-SOX 10调控的位置保守的lncRNA的功能。黑色素瘤是一种侵袭性皮肤癌，来源于一种称为黑素细胞的皮肤细胞的恶性转化，一旦转移，预后不良。假设表型转换为去分化神经嵴干细胞样状态有助于在黑色素瘤中观察到的治疗抗性。在发育过程中，神经嵴细胞产生几种类型的细胞，包括黑素细胞。强调需要进一步了解控制黑色素瘤进展的分子机制及其相关的发展计划，以提供新的治疗靶点和改善预后。研究将集中于鉴定人类（智人）和斑马鱼（斑马鱼）基因组中位置保守的MITF-SOX 10调节的lncRNA（目标1）。MITF和SOX 10是两种转录因子，它们调节参与神经嵴分化、黑素细胞发育和人类黑色素瘤的基因表达程序。这是一个必要的初始步骤，将提供新的见解，在黑色素瘤的发展和致癌事件过程中的基因表达程序的分子机制，提供候选lncRNA优先进一步研究。为了确定候选lncRNA在神经嵴分化和黑素细胞发育过程中的功能，将在作为体内模型的斑马鱼中减弱lncRNA的表达（目的2）。相关体内模型的使用将允许鉴定对不同发育阶段的神经嵴分化和黑素细胞发育重要的lncRNA。通过这些实验，可以评估和表征不同lncRNA的分子功能。最后，为了确定所鉴定的候选lncRNA是否与人类健康临床相关，在体外减弱人类黑素瘤细胞系中的lncRNA表达（目的3）。通过这一目标，可以评估lncRNA在黑色素瘤背景下对人类健康的影响。提供新的治疗靶点和生物标志物，可用于改善黑色素瘤治疗。这些目标的结果将使我们更好地理解lncRNA的功能及其影响神经嵴分化、黑素细胞发育和黑色素瘤基因表达的分子机制。这项拟议的工作体现了BBSRC的优先领域之一：“综合了解健康的生物科学”。