Gill Center for Biomolecular Science

Phone:

812-856-2524

Email:

yylai@indiana.edu

Department:

Psychological and Brain Sciences

Campus:

IU Bloomington

Education:

Ph.D., Yale University School of Medicine, 1986

Research interests:

My research has been focused on developing novel therapeutic strategies for the treatment of neurological disorders using disruptors of protein-protein interactions. Most physiological and pathological signaling occurs via interactions between proteins in signaling complexes. Disruption of protein-protein interaction was long considered an intractable small molecule target because many protein-protein interactions occur over large surface areas. My protein-targeting group at ICOS Corporation (Bothell, WA) focused on therapeutic targets where the basic science suggested that protein-protein interactions are critical, but traditional approaches seeking inhibitors of enzyme function or blockade of receptor function failed to identify practical therapeutics. I have continued this research at Indiana University, focusing on developing a novel set of small molecule protein-protein interaction disruptors that inhibit the signaling process downstream of the excitatory glutamate receptor subtype NMDAR. While NMDA receptor antagonists show efficacy in many neurological disorders, the global blockage of receptor function also led to serious side effects. Disruption of protein-protein interactions downstream of NMDAR activation offers a novel approach to attenuate the consequences of pathological NMDAR activation with fewer side effects. In collaboration with Dr. Andrea Hohmann at the Gill Center for Biomolecular Science, we demonstrated that these protein-protein interaction inhibitors are efficacious in treating chronic pain without the side effects associated with NMDAR antagonists. More recently, we collaborated with Dr. Anantha Shekhar (IU School of Medicine) to show that these inhibitors are also efficacious in treating certain anxiety disorders. Dr. Shekhar and I co-founded Anagin LLC (Indianapolis, IN) to further develop these inhibitors into drug development candidates.

Media links:

• PBS Update—Inching toward a cure
• PBS Update—PTSD at the crossroads

Representative publications:

• Courtney MJ, Li LL, Lai YY. Mechanisms of NOS1AP action on NMDA receptor-nNOS signaling. Front Cell Neurosci. 2014; 8:252.
• Lee WH, Xu Z, Ashpole NM, Hudmon A, Kulkarni PM, Thakur GA, Lai YY, Hohmann AG. Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics. Neuropharmacology. 2015 Oct; 97:464-75.
• Florio SK, Loh C, Huang SM, Iwamaye AE, Kitto KF, Fowler KW, Treiberg JA, Hayflick JS, Walker JM, Fairbanks CA, Lai Y. Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents. Br J Pharmacol. 2009 Sep; 158(2):494-506.