Targeting cell-type specific disease phenotypes to promote CNS repair

项目摘要/摘要 尽管进行了数十年的密集研究，但目前还没有治疗脊髓的疾病修正疗法 损伤(SCI)。这种严重的未得到满足的需求的一个主要原因是细胞的时空异质性 包括受伤部位。靶向一种细胞类型的治疗性分子(如小分子、RNA、蛋白质) 可能是另一种细胞类型的禁忌，从而掩盖了任何潜在的有益影响。在这份提案中， 我们将利用脊髓损伤部位的单细胞转录组学和蛋白质组学数据来解决这个问题 用生物信息学鉴定被预测能逆转细胞类型和疾病表型的化合物 特定于单元状态的方式。我们的研究团队最近开发了一种新型药物发现平台， 将单细胞基因表达数据与来自美国国立卫生研究院图书馆的扰动反应数据相结合 集成的基于网络的蜂窝特征码(LINCS)L1000数据集，用于识别针对特定目标的化合物 细胞异质性不同的组织中的细胞类型。这项提案将解决的另一个挑战 是一种细胞类型的特异性药物传递。我们将开发一种先进的药物输送系统，能够高度 高效的细胞型靶向递送，在脊髓损伤部位释放刺激响应性药物。这些小说 这些技术将被用来靶向构成脊髓纤维化疤痕的巨噬细胞和成纤维细胞。 损伤部位，这是轴突和少突胶质细胞再生的主要障碍。

PROJECT SUMMARY/ABSTRACT Despite decades of intensive research, there are currently no disease-modifying therapies to treat spinal cord injury (SCI). One major reason for this dire unmet need is the spatiotemporal heterogeneity of the cells that comprise the injury site. Therapeutic molecules (e.g., small molecules, RNAs, proteins) that target one cell type may be contraindicated for another cell type, thereby masking any potential beneficial effects. In this proposal, we will address this issue by utilizing single-cell transcriptomics and proteomics data of the spinal cord injury site to bioinformatically identify compounds that are predicted to reverse the disease phenotype in a cell-type and cell-state-specific manner. Our research team has recently developed a novel drug discovery platform that integrates single-cell gene expression data with perturbation-response data derived from the NIH Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset to identify compounds that target specific cell-types in tissues with diverse cellular heterogeneity. Another challenge that will be addressed in this proposal is that of cell-type specific drug delivery. We will develop an advanced drug delivery system capable of highly efficient cell-type targeted delivery with stimuli-responsive drug release at the spinal cord injury site. These novel technologies will be used to target macrophages and fibroblasts that comprise the fibrotic scar at the spinal cord injury site, which is a major barrier to the regeneration of axons and oligodendrocytes.