# Regulated Protein Degradation

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $318,100

## Abstract

Project Summary
 The broad, long-term objective of this research program is to develop general methods to
conditionally regulate protein function at the level of the protein molecules rather than by targeting the
DNA or mRNA precursors that encode a protein-of-interest. These experimental methods are highly
specific for the targeted proteins and provide rapid and tunable control of protein function using cell-
permeable small molecules. The goal is to engineer small protein domains called destabilizing
domains that are rapidly degraded when expressed in mammalian cells. The instability of destabilizing
domains is faithfully conferred to partner proteins fused to these small domains, allowing researchers to
predictably control the levels of any protein-of-interest. One specific aim of this research program will
provide new destabilizing domains that are derived from human proteins and regulated by FDA-
approved drugs. A second aim of this research is to develop a new method for destabilizing domains to
regulate the secretion of therapeutically useful cytokines and hormones from human cells. A third aim
of this research is the development of a new method for the partner proteins regulated by the
destabilizing domains to be liberated from the regulatory domain only when the entire fusion protein is
stabilized by its cognate ligand. The fourth aim builds upon the biophysics underpinning the
destabilizing domains to develop a new class of genetically encoded biosensors for intracellular second
messenger analytes. The current lack of safe and effective methods to regulate the expression and
biological activity of gene-based therapeutics seriously limits the number and types of diseases that
physicians and scientists can contemplate targeting using cell and gene therapy. New regulation
methods such as the destabilizing domains that are safe and effective will dramatically expand the
universe of diseases that can be targeted for treatment through cell and gene therapy, thus opening
new frontiers for treating human diseases that cannot be addressed using existing methods.

## Key facts

- **NIH application ID:** 10417637
- **Project number:** 1R01GM145715-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** THOMAS James WANDLESS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $318,100
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417637

## Citation

> US National Institutes of Health, RePORTER application 10417637, Regulated Protein Degradation (1R01GM145715-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10417637. Licensed CC0.

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