Research Interests

ASD affects about 78 million people worldwide, making it one of the most prevalent and pressing neurological conditions of our time. Over the past decade, advances in autism genetics have delineated the genetic architecture of ASD, pinpointing hundreds of genes as ASD susceptibility genes. Yet advances in genetic discovery have not been transformed into an actionable understanding of ASD pathology. From linking genes to biology, critical gaps in knowledge remain. One major hindrance in this regard is that we fundamentally do not understand the molecular mechanisms that govern the actions of proteins encoded by ASD-linked genes. The Wang lab seeks to bridge this gap by elucidating the function, regulation, and interaction networks of ASD-associated proteins and their alterations in autism at molecular resolution. Drawing from molecular insights into ASD-associated proteins, we also aim to develop nanobodies capable of precisely modulating protein dynamics and functionality for potential therapeutics.

Recent studies have highlighted the profound yet poorly understood connection between cholesterol—along with many other lipid species—and ASD. Beyond the common co-occurrence of ASD and cholesterol dysregulation in patients, 76 of the top 232 ASD-risk genes are either regulated by cholesterol or involved in its regulation. Cholesterol could be crucial in ASD development, and our ongoing research will define its role. 

Scientific Contributions

1 Molecular mechanisms and therapeutic targeting of lipid-related proteins in Hedgehog signaling: In collaboration with Professor Yifan Cheng’s lab at UCSF, Dr. Wang and colleagues performed structure-based analyses to elucidate how the Dispatched protein releases the lipid-modified Hedgehog protein (Nature, 2021). A 2.5 Å Dispatched structure, the highest resolution achieved for an RND transporter by cryo-EM, reveals three Na⁺ ions within its transmembrane domain. By integrating this structural insight with protein dynamics analysis and a nanoluciferase-based assay, they identified Na⁺ as the chemiosmotic driver of Dispatched function. This is the first and only structure to capture ion flux in the act of powering an RND transporter, uncovering a unique cation-binding mechanism for eukaryotic RNDs. The team also resolved a 2.7 Å structure of Dispatched bound to Hedgehog, revealing a unique protein-protein interaction facilitated by a Furin-cleaved linker arm of Dispatched, thus defining the role of Furin cleavage in Dispatched function. Building on these mechanistic insights and her ongoing studies of lipid-related processes in Hedgehog signaling, Dr. Wang has also developed nanobodies (single-domain antibodies) as targeted therapeutic agents to modulate Hedgehog signaling.

2 Intestinal muscle tissue engineering to treat SBS: Dr. Wang created functional human-made intestinal muscle tissue as a potential treatment for short bowel syndrome, an incurable, life-threatening condition. Advances in intestinal muscle regeneration have historically been hampered by inadequate in vitro culture conditions. Dr. Wang and colleagues developed the first culture medium (serum-free) that enables sustained spontaneous muscle contractions for over two months (PLoS One, 2018). Unlike natural intestinal muscles that can exhibit diverse motor patterns, most engineered muscles fail to achieve even one reliable contraction mode. Combining this new medium with a 3D bioscaffold, they created the first engineered intestinal muscle patches capable of producing three distinct contraction modes (Advanced Materials, 2023). The contractions are visible to the naked eye. This research represents the first engineered muscle patch capable of effectively breaking down artificial intestinal contents. Highlighted in Advanced Science News and New Scientists, this work holds promise for motility disorder therapies and the reconstruction of fully functional intestines to treat SBS. Patients with gastroschisis are reaching out to the research team, eagerly anticipating its clinical application.

Honors and Awards

Selected Publications

1)Wang, Q.†, Wang, J., Tokhtaeva, E., Li, Z., Martín, M.G., Ling, X.B., Dunn, J.C.Y.† An Engineered living intestinal muscle patch produces macroscopic contractions that can mix and break down artificial intestinal contents. Advanced Materials, Apr;35 (15), e2207255 (2023). †co-corresponding authors

2)Wang, Q.*, Asarnow, D.E.*, Ding K., Mann R., Hatakeyama J., Zhang, Y., Ma, Y., Cheng, Y., Beachy, P.A. Dispatched uses Na+ flux to power lipid-modified Hedgehog release. Nature 599 (7884), 320-324 (2021). *co-first authors

3)Wang, Q., Wang, K., Solorzano-Vargas, R.S., Lin, P.Y., Walthers, C.M., Thomas, A., Martín, M.G., Dunn, J.C.Y. Bioengineered intestinal muscularis complexes with long-term spontaneous and periodic contractions. PLoS One 13, 1–29 (2018).