# Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $646,000

## Abstract

PROJECT SUMMARY
 Aberrant glial activation is a prominent feature in neurodegenerative diseases. But, what triggers glial
activation in the aging brain and how it contributes to neuronal degeneration remains unclear. The scientific
premise of this proposal is based on previous studies that dominant mutations in human Progranulin gene
(GRN [gene], PGRN [protein]) cause a drastic reduction in PGRN levels in CSF and brain tissues in patients
with frontotemporal lobar degeneration (FTLD), leading to profound gliosis, aggregation of RNA binding protein
TDP-43, and neurodegeneration. In support of this idea, our recent studies show that Grn knockout (Grn-/-)
mice is a valid model that captures several key disease features in FTLD caused by GRN mutations (FTLD-
GRN), including microglial activation, microglia-mediated synaptic pruning and dysfunction in the
thalamocortical circuit. Our ongoing work further revealed that Grn-/- mice and FTLD-GRN patients also shows
a robust astroglial activation that positively correlates with microglial activation. Similar to Grn-/- microglia, Grn-/-
astrocytes exhibit an age-dependent up-regulation of innate immunity genes, including complements C3 and
C4b, which together with C1qa from Grn-/- microglia, activate both classical and alternative complement
pathways to promote neurodegeneration. Taken together, these results support the hypothesis that PGRN
deficiency is a feasible disease model to uncover the intricate neuroimmune interactions and how perturbation
to these interactions leads to neuronal degeneration. To test this hypothesis, we propose a comprehensive
single cell transcriptomic approach to survey the dynamic changes of glial and neuronal cell types in the
thalamocortical circuit that is most severely impacted by PGRN deficiency. This approach will provide critical
insights into the intrinsic mechanism of glial activation, neuronal degeneration and neural circuit dysfunction in
Grn-/- mice and in FTLD-GRN patients. This innovative strategy involves high throughput profiling of
transcriptomic and physiological properties of glia and neurons using droplet-based capture technology,
microscopy and dynamic imaging of cell intrinsic physiological responses. These results will provide an
unprecedented resolution to directly test the hypothesis that disruptions to the dynamic neuroimmune
interactions between microglia, astrocytes and neurons in the thalamocortical circuit lead to neurodegeneration
in FTLD caused by PGRN deficiency.

## Key facts

- **NIH application ID:** 10207374
- **Project number:** 5R01AA027074-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $646,000
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207374

## Citation

> US National Institutes of Health, RePORTER application 10207374, Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD (5R01AA027074-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10207374. Licensed CC0.

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