# Evaluation of TFAP4 regulation of lysosome biogenesis and modulation of tau pathology

> **NIH NIH F31** · YALE UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Millions of individuals are afflicted with Alzheimer’s disease and related tauopathies, and with our aging
population, the occurrence of these devastating diseases will continue to increase, posing an immense burden
on our healthcare system. Tauopathies are marked by the accumulation of toxic tau species leading to
progressive neuron loss. Impairments in the autophagy-lysosome pathway (ALP), an essential cellular process
used to clear waste, recycle resources, and maintain homeostasis, have been reported across
neurodegenerative diseases contributing to the build-up of toxic protein species. Strategies to promote the
activity of the ALP could prevent the formation or enhance the clearance of these inclusions and offer therapeutic
benefits for many neurodegenerative diseases including tauopathies where there is a need for effective treatment
options. Our lab recently found nemo-like kinase acts as a negative regulator of the lysosome and that reduction
of the protein is able to ameliorate neurodegenerative phenotypes. Upon further investigation into this signaling
pathway, we identified TFAP4 as a potential transcriptional regulator of lysosome biogenesis and function. In
vitro studies revealed TFAP4 overexpression was able to increase transcription of genes belonging to the
coordinated lysosomal enhancement and regulation (CLEAR) network, increase levels of lysosome-associated
proteins, increase lysosome number and size, and increase lysosomal hydrolytic activity. For this proposal, we
generated cell-type specific Cre-inducible TFAP4 overexpression and knock-out mice that will allow us to
evaluate the role of TFAP4 towards lysosome biogenesis and function in healthy and diseased neuronal
populations in vivo. Specific aim 1 will be used to better understand the molecular mechanisms underlying TFAP4
activity through the use of molecular, biochemical, histological, and transcriptomic approaches to confirm
lysosomal alterations in vivo and identify the gene targets of TFAP4. Specific aim 2 will allow us to evaluate the
therapeutic potential of TFAP4 modulation using a tauopathy mouse model where we will look for pathological
changes including alterations in hyperphosphorylated tau, neurofibrillary tangle formation, and synapse number
as well as behavioral changes in cognition and working memory. The completion of these research aims in
combination with my proposed training plan will provide me with a strong foundation to embark on a career as
an independent researcher investigating the mechanisms underlying neurodegeneration.

## Key facts

- **NIH application ID:** 11066701
- **Project number:** 1F31NS141258-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ashley Owens
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11066701

## Citation

> US National Institutes of Health, RePORTER application 11066701, Evaluation of TFAP4 regulation of lysosome biogenesis and modulation of tau pathology (1F31NS141258-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11066701. Licensed CC0.

---

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