Targeting cell-type specific disease phenotypes to promote CNS repair

NIH Pandemic-Era Grants

Pandemic Era Grants

2023

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Principal Investigator: NAGI G AYAD
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2023
Award: $1,320,578
Funding agency: National Institute of Neurological Disorders and Stroke

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.

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