The most intractable diseases of our time, from Alzheimer’s and Parkinson’s to ALS, share a common thread: cells that can no longer clean house. Damaged proteins and organelles accumulate, homeostasis deteriorates, and chronic inflammation can set off a vicious cycle of degeneration. I want to understand how cells decide what to repair, what to throw out, how they take out the trash, and then control those decisions with small molecules.
Current projects
How the autophagy machinery shuts down an immune alarm
The autophagy machinery is best known for building autophagosomes, which engulf cellular waste and carry it to the lysosome. We found that cells co-opt this same machinery for an entirely different job: switching off innate immune signaling.
STING is one of the cell’s alarms. It goes off when DNA shows up where it shouldn’t, a sign of infection or damage. Just like turning off the fire alarm when the threat is gone so we can go back into the office, cells need to silence STING to get back to their normal work. We discovered that the autophagy machinery does this by delivering activated STING from the Golgi to the endolysosome for destruction. When that delivery fails, STING keeps signaling and cells are left in a constant inflammatory state.
This opens up a series of questions I am currently pursuing:
- What else does the cell send down this route from the Golgi to the lysosome?
- How does it go awry in neurodegeneration, autoimmunity, and cancer?
- Can we drug it?
Rewiring autophagy with small molecules
Autophagy is uniquely important in long-lived, non-dividing neurons, yet the machinery has remained exceptionally difficult to drug. It works inside the cell, largely through transient protein–protein and protein–membrane interactions, with few conventionally druggable enzymes. Drugging members of this pathway is a challenge, but also an opportunity to expand therapeutically targetable space.
At the Center for Alzheimer’s and Related Dementias, I initiated and lead a program to rewire the autophagy machinery with small molecules. Along the way I have run several drug discovery campaigns. This has led me and the group to think about clever ways to hasten this expensive and time-consuming endeavor. The goal is brain-penetrant chemical matter that restores cellular recycling and protects vulnerable neurons.
How mitophagy drugs actually work
Activating PINK1/Parkin mitophagy, the removal of damaged mitochondria, is one of the leading strategies for treating Parkinson’s disease. For my PhD with Tsui-Fen Chou and David Chan at Caltech, I asked how two reported activators of the pathway actually work. Both increased mitophagy, but not by activating PINK1 or Parkin directly. Instead, they behaved as weak mitochondrial toxins that sensitize cells to stress. It’s a bit like smashing a broken appliance into smaller pieces when what you really want is to have it hauled away. The lesson for drug discovery is that our screens need to detect the difference between enhancing the hormetic response vs triggering it via damage. Science Advances, 2025 · Caltech news
I also contributed to work showing how the immune regulator TNIP1 puts the brakes on selective autophagy (Molecular Cell, 2023).
Mitochondrial channels, one molecule at a time
At the NIH (NICHD) with Sergey Bezrukov and Tatiana Rostovtseva, I used single-molecule electrophysiology to study the voltage-dependent anion channel (VDAC), the main gateway for metabolites and calcium across the mitochondrial outer membrane. We showed how VDAC2’s conformational plasticity controls its interactions with cytosolic proteins (Science Advances, 2025) and how the three VDAC isoforms distinctly shape mitochondrial function and metabolism (JBC, 2026). We also studied how the protein α-synuclein and drugs such as olesoxime and efsevin regulate the channel.
Across scales
KLF4 and mitophagy
Showed that cells lacking the transcription factor KLF4 have mitochondrial dysfunction and impaired mitophagy.
Chromatin in nanochannels
Single-molecule imaging and polymer-physics modeling of megabase-long chromatin confined to nanofluidic channels.
Where it started
As a high-school researcher, I used stable-isotope mass spectrometry in Drosophila to detect changes in mTOR signaling and autophagy.
Methods
- Single-molecule electrophysiology
- Cell biology
- Protein biochemistry
- Planar lipid bilayers
- X-ray crystallography
- Protein NMR
- Mass-spec proteomics
- Confocal & fluorescence microscopy
- Hit-to-lead drug discovery
- Statistical-physics modeling
- Python · MATLAB