Connexins and glioblastoma progression

 描述(由申请人提供)：胶质母细胞瘤(GBM)是最常见的恶性脑癌类型，尽管不断有研究开发新的治疗方法，但它通常是致命的。GBM致死率高的一个原因是存在一种对化疗和放射治疗具有抵抗力的自我更新的细胞群，称为癌症干细胞(CSCs)。尽管癌症干细胞假说仍然存在争议，但我们和其他人已经表明，直接靶向这一群体的细胞可以减少肿瘤的生长和起始，并使肿瘤对当前的临床治疗敏感。CSC内以及CSCs与非CSCs之间的细胞相互作用有助于维持CSC自我更新和分化之间的平衡。直接的细胞相互作用也可能使细胞对肿瘤生长和化疗药物的存在做出快速适应。缝隙连接是一种细胞-细胞接触机制，由形成连接蛋白通道的连接蛋白亚基组成，连接蛋白通道允许小分子在细胞间运输。这个项目的翻译目标是引导对细胞-细胞相互作用在GBM进展中的作用的机制研究。我们假设，细胞类型特异的通讯是由连接蛋白亚基的平衡控制的，破坏这种平衡会减弱基底膜的进展。我们将通过研究以下目标来验证这一假说：1)连接蛋白亚基之间的平衡对CSCs、非CSCs和正常神经细胞产生不同的影响；2)Cx46有助于CSC的维持；3)体内靶向连接蛋白亚单位可以减缓GBM的进展。该项目的长期目标是将获得的有关Direct的信息 基底膜中的细胞间通讯对抑制策略有用，可用于临床治疗。

 DESCRIPTION (provided by applicant): Glioblastoma (GBM), the most common type of malignant brain cancer, is uniformly fatal despite ongoing research into the development of novel therapeutics. One reason for the high lethality of GBM is the presence of a self-renewing population of cells that is resistant to chemo- and radiation therapy, termed cancer stem cells (CSCs). Although the cancer stem cell hypothesis remains controversial, we and others have shown that directly targeting this population of cells decreases tumor growth and initiation and sensitizes tumors to current clinical therapies. Cellular interactions within the CSC compartment and between CSCs and non-CSCs help maintain the balance between CSC self-renewal and differentiation. Direct cell interactions may also allow cells to rapidly adapt in response to tumo growth and the presence of chemotherapeutics. Gap junctions, one type of cell-cell contact mechanism, are composed of connexin subunits that form connexon channels, which allow the transport of small molecules from cell to cell. The translational goal of this project is to conduc mechanistic studies into the role of cell-cell interactions in the progression of GBM. We hypothesize that cell type-specific communication is controlled by a balance of connexin subunits and that disrupting this balance attenuates GBM progression. We will interrogate this hypothesis by investigating the following aims: 1) that the balance between connexin subunits exerts differential effects on CSCs, non-CSCs, and normal neural cells; 2) that Cx46 contributes to CSC maintenance; and 3) that in vivo targeting of connexin subunits attenuates GBM progression. The long-term goal of this project is to translate the information gained about direct cell-cell communication in GBM to inhibition strategies useful as clinical therapies.