Identification of molecular-neuropathological signatures in AD, FTLD and Long COVID - PROJECT SUMMARY/ABSTRACT Neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), exhibit neuropathological features (e.g., amyloid and p-tau accumulation) that disproportionately affect certain brain regions and subsets of cells. This selective vulnerability to neuropathological features has been recognized for decades, yet its underlying molecular mechanisms remain unclear. Long COVID, a prevalent post-pandemic condition with largely unknown disease mechanisms, is reported to exhibit p-tau pathology, linking it to neurodegeneration. Current methods, including single-nucleus RNA sequencing, are unable to integrate spatial and pathological contexts with transcriptomic profiles, limiting direct molecular characterization of disease pathology at the single cell level. Here, I propose to leverage single-cell spatial multi-omics on postmortem brain tissues to in-situ capture molecular and cellular alterations that directly linked to selective vulnerability to neuropathological features across AD, FTLD, and Long COVID at single-cell resolution—insights previously unattainable. I will also identify potential pathological modulators using functional genomics in human induced pluripotent stem cell (iPSC)-derived neurons. In this proposal, Aim1 will characterize neuropathological and transcriptomic alterations in Long COVID and compare findings to AD and FTLD. Aim2 will leverage same- slide single-cell spatial multi-omics with neuropathology phenotyping (Xenium 5K + Phenocycler-Fusion) and define the molecular-neuropathological signatures specific to amyloid, neuronal p-tau, and glial p-tau pathology in AD, FTLD and Long COVID. Aim3 will employ CRISPRi/a screening in iPSC-derived neurons to identify neuronal p-tau modifiers from signatures uncovered in Aim2. By integrating single-cell spatial multi-omics with functional genomics, this project will bridge the gap between neuropathology and molecular profiling, provide novel insights into selective vulnerability to neuropathological features and identify pathological modulators. My long-term goal is to become a physician(neuropathologist)-scientist leading a NIH-funded research laboratory focused on neurodegenerative diseases and COVID-19. This five-year mentored career development plan will provide the necessary training for my transition to independence, emphasizing expertise in single-cell spatial transcriptomics and proteomics, bioinformatics, imaging analysis, iPSC technology and CRISPR-based functional genomics. Additionally, I will deepen my knowledge of neuropathology, molecular genetics, and clinical aspects of AD, FTLD, and Long COVID. I have assembled a multidisciplinary mentorship team of distinguished physician-scientists that includes Dr. Daniel Geschwind (primary mentor), Drs. Harry Vinters and Shino Magaki (co-mentors), and advisory members Drs. Inma Cobos, Vivek Swarup, and Edward Lee. With UCLA's cutting- edge facilities, exceptional research environment, and strong clinical resources, this award will prepare me to become a competitive neuropathologist-scientist, advancing our understanding of neurodegenerative diseases and COVID-19 while informing therapeutic strategies.
