# Characterizing Vulnerable Cell Types in C9orf72-FTD

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2022 · $51,752

## Abstract

Project Summary/Abstract
C9orf72 expansion mutations are the most common genetic cause of frontotemporal dementia (C9-FTD), a
fatal and incurable neurodegenerative disease. C9-FTD is most commonly neuropathologically characterized
by frontotemporal lobar degeneration (C9-FTLD) and the accumulation of phospho-TDP-43 (pTDP-43)
inclusions in neurons and glia. In C9-FTLD, the medial orbitofrontal cortex (mOFC) is affected early in the
disease course, and individuals with mOFC lesions phenocopy patients with FTD, suggesting that mOFC
dysfunction impacts FTD clinical phenotypes. In disease, the mOFC exhibits pTDP-43 inclusions, neuronal
degeneration, and neuroinflammation, including the development of pathologic microglia. In other diseases,
pathologic microglia increase extracellular glutamate and induce death in excitatory neurons. However, these
factors’ relative contributions to C9-FTLD pathogenesis are not well understood, and the molecular profiles of
degenerating neurons (termed vulnerable neurons) and pathologic microglia in the mOFC are unknown.
We hypothesize that in C9-FTLD, pathologic microglia contribute to the selective degeneration of
vulnerable populations of excitatory neurons, resulting in dementia. This proposal aims to use
transcriptomic methods to identify vulnerable neuron and pathologic microglia subtypes and characterize their
molecular profiles, spatial distributions, and interactions that may be contributing to disease progression. To
this end, Aim #1 will use single-nucleus RNA sequencing to identify and characterize the pathologic microglia
subtypes that arise and the vulnerable neuron subtypes that degenerate in C9-FTLD. Cellular proximity is the
basis for intercellular interactions, and Aim #2 will use spatial transcriptomics to identify where these pathologic
microglia and vulnerable neurons are spatially distributed as well as their spatial proximities in relation to each
other and to pTDP-43 inclusions.
A better understanding of how C9-FTLD changes neurons’ and microglia’s gene expression patterns, their
spatial distributions, and their interactions may lead to strategies to protect cells from disease and patients
from dementia. These studies will emphasize how pathologic microglia can contribute to neurodegeneration,
enabling the development of microglia-targeted therapies for C9-FTD and other neurodegenerative diseases.
Through this project, I will develop expertise in the use of histological and computational techniques. My
sponsor, Dr. Edward Lee, is committed to my training and success as a physician-scientist.

## Key facts

- **NIH application ID:** 10464266
- **Project number:** 1F30AG077858-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David Dai
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 1
- **Project period:** 2023-01-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464266

## Citation

> US National Institutes of Health, RePORTER application 10464266, Characterizing Vulnerable Cell Types in C9orf72-FTD (1F30AG077858-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10464266. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*