Elucidating the Role of MiR-31 in Retinoblastoma Invasion

描述（申请人提供）：更深入地了解miRNA异常表达如何影响视网膜母细胞瘤的临床和病理特征，可以为癌症治疗提供新的治疗靶点。我们的长期目标是确定视网膜母细胞瘤中发生的遗传变化，以便有效地利用这些信息进行靶向治疗。本研究的目标是建立miRNA表达与视网膜母细胞瘤侵袭之间的联系，以确定新的治疗靶点，这是我们实现长期目标的下一步。我们的中心假设是，由于关键靶基因的抑制丧失，miR-31的异常表达可能有助于视网膜母细胞瘤的侵袭。因此，miR-31可以作为视网膜母细胞瘤治疗的可行靶点。本研究的基本原理是更好地了解异常miR-31和靶基因表达如何促进视网膜母细胞瘤的侵袭，从而确定视网膜母细胞瘤的治疗靶点，并更好地了解与侵袭和转移相关的机制。我们计划通过追求以下具体目标来验证我们的中心假设：(1)确定miR-31在视网膜母细胞瘤侵袭中的作用。我们将通过分析miR-31在人视网膜母细胞瘤肿瘤和分离的侵袭性人视网膜母细胞瘤细胞中的表达来实现这一特定目标。此外，将在体外和体内操作视网膜母细胞瘤细胞系中miR-31的表达，以确定其侵袭能力的变化。(2)验证miR-31促进视网膜母细胞瘤侵袭的潜在靶点。我们将通过确定miR-31表达对潜在靶点的影响，并通过测量侵犯视神经和其他眼内结构的视网膜母细胞瘤细胞中的靶蛋白表达来实现这一特定目标。我们还将独立操纵靶基因表达，并与miR-31表达相关，以确定细胞侵袭的变化。期望我们在这项研究中的贡献将是提供对异常miRNA表达如何促进视网膜母细胞瘤侵袭的详细了解。这一贡献意义重大，因为它是视网膜母细胞瘤遗传变化鉴定连续研究的重要一步，可以作为开发新疗法的目标。我们认为，拟议的研究具有创新性，因为它将解决两个重要但尚未得到充分研究的主题：(1)视网膜母细胞瘤侵袭的基本机制，以及(2)miRNAs如何促进视网膜母细胞瘤的重要临床和病理特征。这项拟议的研究与公共卫生有关，因为对miRNA异常表达如何促进肿瘤进展的更好理解不仅适用于视网膜母细胞瘤，也适用于其他癌症。因此，从本研究中了解到的信息可以为化疗干预提供新的靶点，以防止或减缓转移性视网膜母细胞瘤的进展。此外，这一知识可以为肿瘤侵袭和转移的相关机制提供新的见解。

DESCRIPTION (provided by applicant): A greater understanding of how aberrant miRNA expression contributes to clinical and pathological characteristics of retinoblastoma could provide novel therapeutic targets for cancer treatment. Our long-term goal is to identify genetic changes that occur in retinoblastoma in order to effectively use that information to target therapy. The objective for this study, which is the next step toward the attainment of our long-term goal, is to establish the link between miRNA expression and retinoblastoma invasion for the identification of novel therapeutic targets. Our central hypothesis is that aberrant miR-31 expression could be instrumental in retinoblastoma invasion due to the loss of inhibition of key target genes. For this reason, miR-31 could serve as a viable target for retinoblastoma treatment. The rationale for this proposed research is that a better understanding of how aberrant miR-31 and target gene expression contribute to retinoblastoma invasion could lead to the identification of therapeutic targets for retinoblastoma, and lead to a greater understanding of the mechanisms associated with invasion and metastasis in general. We plan to test our central hypothesis by pursuing the following specific aims: (1) To define the role of miR-31 in retinoblastoma invasion. We will pursue this specific aim by analyzing miR-31 expression in human retinoblastoma tumors and isolated invasive human retinoblastoma cells. Further, miR-31 expression will be manipulated in retinoblastoma cell lines in vitro and in vivo in order to determine changes in invasive capacity. (2) To validate the potential miR-31 targets that promote invasion of retinoblastoma. We will pursue this specific aim by determining the effect of miR-31 expression on potential targets, and by measuring target protein expression in retinoblastoma cells invading the optic nerve and other intraocular structures. We will also manipulate target gene expression independently and in relation to miR-31 expression to determine changes in cell invasion. It is expected that our contribution in this proposed research study will be to provide a detailed understanding of how aberrant miRNA expression contributes to retinoblastoma invasion. This contribution will be significant because it is an important step i a continuum of research involving the identification of genetic changes within retinoblastoma that can be targeted for the development of novel therapies. The proposed research is innovative, in our opinion, because it will address two important but understudied topics: (1) Mechanisms essential to retinoblastoma invasion, and (2) How miRNAs contribute to important clinical and pathologic characteristics of retinoblastoma. The proposed research is relevant to public health because a greater understanding of how aberrant miRNA expression contributes to tumor progression will apply not only to retinoblastoma, but to other cancers as well. As such, what is learned from this research could provide novel targets for chemotherapeutic intervention to prevent or slow the progression to metastatic retinoblastoma. Further, this knowledge could provide new insights into the mechanisms associated with tumor invasion and metastasis across cancer types.