Targeting cell-type specific disease phenotypes to promote CNS repair

项目总结/摘要 尽管进行了数十年的深入研究，但目前还没有治疗脊髓疾病的疾病修饰疗法 损伤（SCI）。这种迫切的未满足需求的一个主要原因是细胞的时空异质性， 包括损伤部位。治疗分子（例如，小分子、RNA、蛋白质），靶向一种细胞类型 可能禁忌用于另一种细胞类型，从而掩盖任何潜在的有益效果。在这一提议中， 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 以生物信息学方式鉴定预测可逆转细胞类型中疾病表型的化合物， 细胞状态特异性方式。我们的研究团队最近开发了一个新药发现平台， 将单细胞基因表达数据与来自NIH文库的扰动响应数据相结合， 集成的基于网络的细胞特征（LINCS）L1000数据集，用于识别靶向特定化合物 具有不同细胞异质性的组织中的细胞类型。本提案将解决的另一个挑战是 是细胞类型特异性药物递送。我们将开发一种先进的药物输送系统， 在脊髓损伤部位具有刺激响应性药物释放的有效细胞型靶向递送。这些新颖 技术将用于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.