# Modulation of Cellular Clearance to Treat Human Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $346,719

## Abstract

The goal of this project is to gain a deeper knowledge on the mechanisms that regulate the lysosome in an
effort to identify novel tools to regulate its function. This knowledge could have a direct impact on the
development of therapeutic options for lysosomal storage diseases (LSDs), a group of over 50 inherited
diseases with a progressive and multisystemic phenotype, which mostly affect children. In 2009 we
discovered that lysosomal function and autophagy are subject to a global transcriptional regulation, which is
mediated by the master gene TFEB (Sardiello et al. Science 2009; Settembre et al. Science, 2011). This
regulatory pathway allows the lysosome to respond to environmental cues such as starvation, physical
exercise, infection, and a variety of stress conditions. TFEB mediates a lysosome-to-nucleus signaling
mechanism that originates from the lysosomal surface and is regulated by the mTORC1 kinase. Induction
lysosomal biogenesis and autophagy via TFEB has proven to be a potent tool to promote cellular clearance in
LSDs and neurodegenerative diseases (Medina et al, Dev Cell,2011, Decressac et al, PNAS, 2013). In spite
of these exciting developments several knowledge gaps remain in our understanding of how TFEB is
regulated at both transcriptional and post-translational levels and on how we could be modulate lysosomal
function and cellular clearance to treat human diseases. This project aims at tackling these gaps by: 1)
dissecting the molecular and developmental cues responsible for TFEB transcriptional regulation and on the
definition of TFEB epigenetic landscape in steady-state conditions; 2) identifying the pathways that mediate
TFEB nuclear export and the players involved. A deeper understanding of these pathways may lead to the
identification of tools (and potential targets) to either inhibit or enhance TFEB nuclear export and 3) studying
pathways alternative to TFEB that regulate lysosomal function in an effort to identify novel signalling pathways
and molecules that regulate, either directly or indirectly, lysosomal function. The results of these studies will be
instrumental in identifying new strategies and tools to safely and effectively modulate clearance of lysosomal
storage in a variety of diseases.

## Key facts

- **NIH application ID:** 10021456
- **Project number:** 5R01NS078072-09
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** ANDREA BALLABIO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2012-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021456

## Citation

> US National Institutes of Health, RePORTER application 10021456, Modulation of Cellular Clearance to Treat Human Disease (5R01NS078072-09). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10021456. Licensed CC0.

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