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Targeting cell-type specific disease phenotypes to promote CNS repair

针对细胞类型特异性疾病表型促进中枢神经系统修复

基本信息

批准号：
10718222
负责人：
NAGI G AYAD
金额：
$ 132.06万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718222
关键词：
Address Attenuated Behavioral Bioinformatics Cell surface Cells Cicatrix Data Data Set Disease Drug Delivery Systems Fibroblasts Fibrosis Gene Expression Gene Expression Profile Goals Heterogeneity Hybrids In Vitro Individual Injury Laboratories Libraries Macrophage Malignant Neoplasms Microfluidics Modality Modeling Mus Nanotechnology Natural regeneration Network-based Neurons Oligodendroglia Pathology Pharmaceutical Preparations Phenotype Polymers Process Proteins Proteomics RNA Recovery Reporting Research Site Specificity Spinal cord injury Stimulus Testing Therapeutic Tissues Treatment Efficacy United States National Institutes of Health Work axon growth axon regeneration cell type disease phenotype drug discovery in vivo evaluation lipid nanoparticle mouse model nanoparticle nanoparticle drug nervous system disorder new technology novel novel therapeutics repaired response single-cell RNA sequencing small molecule spatiotemporal targeted delivery therapeutic target therapeutically effective tool transcriptomics virtual

项目摘要

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.

项目概要/摘要尽管经过数十年的深入研究，目前尚无治疗脊髓的疾病缓解疗法损伤（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。针对一种细胞类型的治疗分子（例如小分子、RNA、蛋白质）可能对另一种细胞类型是禁忌的，从而掩盖了任何潜在的有益作用。在这个提案中，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以生物信息学方式识别预计可逆转细胞类型疾病表型的化合物，细胞状态特定的方式。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 NIH 图书馆的扰动响应数据整合在一起基于集成网络的细胞特征 (LINCS) L1000 数据集，用于识别针对特定目标的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细胞类型特异性药物输送。我们将开发一种先进的药物输送系统，能够高度在脊髓损伤部位进行有效的细胞型靶向递送和刺激响应性药物释放。这些小说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是轴突和少突胶质细胞再生的主要障碍。