Focus on Dicer inhibition as a novel treatment for brain tumors

专注于 Dicer 抑制作为脑肿瘤的新型治疗方法

基本信息

批准号：
9056040
负责人：
Mohanish P Deshmukh
金额：
$ 22.8万
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：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056040
关键词：
Age Biogenesis Brain Brain Neoplasms Brain region Cell Death Cells Cerebellar degeneration Cerebellum Childhood Brain Neoplasm Childhood Cerebellar Neoplasm Cytoplasmic Granules DNA Damage DNA Double Strand Break DNA Repair Development Engineering Erinaceidae Failure Goals Hela Cells Human Knock-out Maintenance Measures Mediating MicroRNAs Modeling Mus Neurons Outcome Pathway interactions Plants Pre-Clinical Model Proliferating Publishing Radiation therapy Role Sampling Site Stem cells Stress Tamoxifen Testing Time Tissue Microarray Toxic effect Tumor Burden Untranslated RNA base experience genome integrity human DICER1 protein in vivo killings medulloblastoma mouse model neoplastic cell nerve stem cell neurotoxicity novel postnatal public health relevance research study response smoothened signaling pathway therapeutic target tumor tumor growth virtual

项目摘要

DESCRIPTION (provided by applicant): The focus of our proposal is to evaluate whether Dicer inhibition is an effective strategy to selectively target medulloblastoma cells while sparing neurons. While the microRNA-dependent functions of Dicer are well known, recent studies have identified a novel, microRNA-independent function of Dicer in DNA damage repair. As maintenance of genomic integrity is critical for rapidly dividing cells that experience constitutiv replicative stress-induced DNA damage, we evaluated whether Dicer was essential for resolving such DNA damage in vivo in the context of developing cerebellum. In the absence of Dicer, the rapidly dividing cerebellar granule neuron precursors (CGNPs) accumulated DNA damage, which resulted in their degeneration. Remarkably, this degeneration was rescued by p53 deficiency, indicating that Dicer deficiency triggered the activation of the p53-mediated DNA damage pathway. In contrast to the high expression of Dicer in proliferating CGNPs, we found that Dicer is virtually undetectable in cerebellar granule neurons. These results suggest that unlike the proliferating CGNPs, Dicer may not be essential for survival in postmitotic neurons - a hypothesis we will test in a mouse model where we can conditionally delete Dicer selectively in the postmitotic cerebellar neurons. Importantly, we will also evaluate whether inactivation of Dicer could trigger cell death in medulloblastomas. Medulloblastomas are pediatric cerebellar tumors that arise from the aberrant and sustained proliferation of CGNPs beyond the developmental period. Medulloblastoma cells express Dicer, and we predict that, just as seen with the proliferating CGNPs during development, the proliferating medulloblastoma tumor cells also depend on Dicer for resolving endogenous DNA damage. We will test this hypothesis in two mouse models of medulloblastoma where we can readily assess the outcome of Dicer deletion on tumor growth as well as tumor regression. Together, these experiments critically evaluate the unexpected potential of Dicer as a therapeutic target for medulloblastoma with minimal neurotoxicity.

描述（由适用提供）：我们的提案的重点是评估dicer抑制是否是选择性靶向髓母细胞的有效策略神经元。虽然DICER的microRNA依赖性功能是众所周知的，但最近的研究已经确定了DICER在DNA损伤修复中的一种新型的，无microRNA独立的功能。由于基因组完整性的维持对于经历构成复制胁迫诱导的DNA损伤的快速分裂细胞至关重要，因此我们评估了DICER在发展小脑的情况下是否对于在体内解决这种DNA损伤至关重要。在没有迪切尔的情况下，迅速分裂的小脑颗粒神经元前体（CGNP）会累积DNA损伤，从而导致其退化。值得注意的是，这种变性对p53缺陷做出了反应，表明迪切尔缺乏触发了p53介导的DNA损伤途径的激活。与增生的CGNP中迪切尔的高表达相反，我们发现迪切尔在小脑颗粒神经元中几乎无法检测到。这些结果表明，与增殖的CGNP不同，DICER可能对有丝分裂神经元的生存至关重要 - 这是一个假设，我们将在小鼠模型中测试，在小鼠模型中我们可以在丝状小脑神经元中有条件地删除DICER。重要的是，我们还将评估dicer失活是否可以触发髓母细胞瘤中的细胞死亡。髓母细胞瘤是小儿小脑肿瘤，它是由CGNP的异常和持续增殖而产生的。髓母细胞瘤细胞表达丁香细胞，我们预测，就像在发育过程中增殖的CGNP所见一样，增殖的髓母细胞瘤肿瘤细胞也依赖于DICER来解决内源性DNA损伤。我们将在两个髓母细胞瘤的小鼠模型中检验这一假设，在其中我们可以轻松地评估dicer缺失对肿瘤生长以及肿瘤回归的结果。这些实验共同评估了DICER作为具有最小神经毒性的髓母细胞瘤的治疗靶标的意外潜力。