# Modulating Alzheimer’s Disease by mTORC1 inhibition to augment lysosomal activity

> **NIH NIH K99** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $122,536

## Abstract

PROJECT SUMMARY/ABSTRACT:
This proposal is in application for a Pathway to Independence Award for Dr. Travis Lear at the Aging Institute at
the University of Pittsburgh. Dr. Lear has extensive experience in the molecular biology of ubiquitination in aging,
inflammation, autophagy, and lysosome biology. This K99/R00 would be a crucial step for Dr. Lear as part of his
career goal of reaching research independence. The focus of Dr. Lear’s future lab will be to study the
mechanisms of protein degradation and lysosomal activity in neurodegeneration in pursuit of uncovering new
therapeutic avenues. Under this K99/R00 award, Dr. Lear would have protected time for additional training in
neurobiology techniques and aging biology, and for career development to facilitate a successful transition to
research independence. This mentorship team of experts in aging, lysosomal, and neurobiology combined with
the scientific environment at the Aging Institute will be ideal for Dr. Lear’s training. The scientific expertise training
will entail 1) in vitro primary tissue culture skill, 2) study of iPSC development, differentiation, and gene-editing,
3) generation and phenotypic characterization of mouse models of neurodegeneration. Dr. Lear’s leadership
training will focus on 1) integration to scientific community through networking, 2) enhancing his mentoring skills,
3) improving grantsmanship. Successful completion of the proposed research and training plan will provide the
knowledge and experience necessary to progress toward Dr. Lear’s career goal of becoming an independent
investigator studying neuronal aging and Alzheimer’s Disease (AD). To accomplish this, Dr. Lear proposes to
study a new mechanism of proteolytic control of lysosomal activation to augment processing of pathogenic tau
protein aggregates in models of AD. Specifically, Dr. Lear has elaborated a model in which a key mTORC1
inhibitor protein, KPTN, is potently controlled by the E3 ubiquitin ligase PDZRN3, which ubiquitinates and fates
KPTN for degradation. Also, unbiased screening yielded a small molecule KPTN activator which increases KPTN
protein level, inhibits mTORC1 activity, and increases lysosomal number and activity. Excitingly,
pharmacological augmentation of KPTN reduces tau protein aggregation in vitro, which has therapeutic
implications for the treatment of Alzheimer’s Disease. The net effect of KPTN augmentation would therefore aid
in clearance of toxic protein aggregates by activation of autophagy. This leads to the central hypothesis that
PDZRN3 control of KPTN affects neuronal lysosomal activity and that genetic or pharmacological
activation of KPTN may be an avenue to reduce tau protein aggregates. Two aims will interrogate this
hypothesis: (1) To examine the mechanism and biologic effect of the PDZRN3-KPTN axis on tau-aggregation in
vitro with inducible pluripotent stem cell (iPSC) and primary cell models, and (2) to examine this mechanism and
effect using genetic and pharmacolog...

## Key facts

- **NIH application ID:** 10505607
- **Project number:** 1K99AG078342-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Travis Bradley Lear
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $122,536
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505607

## Citation

> US National Institutes of Health, RePORTER application 10505607, Modulating Alzheimer’s Disease by mTORC1 inhibition to augment lysosomal activity (1K99AG078342-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10505607. Licensed CC0.

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