Tingting Yang, PhD
- Associate Professor of Ophthalmic Sciences (in Ophthalmology)
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Overview
Academic Appointments
- Associate Professor of Ophthalmic Sciences (in Ophthalmology)
Research
The Yang lab studies the structure, function and regulation of ion channels in the eye, and the pathological mechanisms and treatment of their associated diseases.
Our recent work is focused on a family of calcium (Ca2+)-activated chloride (Cl-) channels named bestrophins, which are widely distributed from bacteria to mammals. Among the four human bestrophin paralogs, bestrophin-1 (Best1) and bestrophin-2 (Best2) have been found in the eye and linked to important (patho)physiological events. Best1 is located in retinal pigment epithelium, playing an essential role in generating a vision-related electrical signal named “light peak”. Over 250 genetic mutations in its encoding gene, BEST1, have been documented to cause a spectrum of at least five retinal degenerative diseases, including the early-onset form of vitelliform macular dystrophy, also known as Best disease. The patients are susceptible to progressive vision loss which may eventually lead to blindness, while no treatment is currently available. Best2 resides in non-pigmented epithelium of the ciliary body, participating in aqueous humor formation and drainage, which determine intra-ocular pressure (IOP). Best2 knockout mice exhibit abnormal aqueous humor homeostasis and a decrease of IOP. Importantly, as IOP must be properly maintained for the normal function of the eye and high IOP is a major risk factor for numerous eye diseases including glaucoma, Best2 represents a promising pharmaceutical target for lowering IOP.
We apply a multidisciplinary platform consisting of cryoEM, crystallography, electrophysiological recording, CRISPR/Cas9-mediated genome editing, and stem cell reprogramming/differentiation. Our previous works include solving the first Best1 and Best2 structures, deciphering their regulatory mechanisms and physiological roles, elucidating disease-causing mechanisms of BEST1 patient-derived mutations, and establishing gene therapy for Best disease.
Grants
STRUCTURAL AND FUNCTIONAL INVESTIGATIONS OF BEST1 PATIENT-DERIVED MUTATIONS (Private)
Jan 1 2021 – Dec 31 2025
THERAPEUTIC GENE EDITING AND MULTIMODAL IMAGING IN JUVENILE MACULAR DEGENERATION (Federal Gov)
Jun 1 2020 – May 31 2025
MECHANISTIC CHARATERIZATION OF CALCIUM-ACTIVATED CHLORIDE CHANNELS IN RETINAL PIGMENT EPITHELIUM (Federal Gov)
May 1 2018 – March 31 2023
INVESTIGATING INTERACTING PARTNERS OF BESTROPHIN CHANNELS (Private)
July 1 2021 – Jun 30 2022
STRUCTURE-FUNCTION ANALYSIS OF BESTROPHINS (Federal Gov)
May 1 2015 – Dec 31 2019
Selected Publications
- Owji AP, Yu K, Kittredge A, Wang J, Zhang Y, Yang T. Bestrophin-2 and glutamine synthetase form a complex for glutamate release. Nature, 2022; https://doi.org/10.1038/s41586-022-05373-x
- Owji AP, Wang J, Kittredge A, Clark Z, Zhang Y, Hendrickson WA, Yang T. Structures and gating mechanisms of human bestrophin anion channels. Nat Commun, 2022 Jul 4;13(1):3836
- Zhao Q, Kong Y, Kittredge A, Li Y, Shen Y, Zhang Y, Tsang SH, Yang T. Distinct expression requirements and rescue strategies for BEST1 loss- and Gain-of-function mutations. eLife, 2021; 10: e67622
- Owji AP, Zhao Q, Ji C, Kittredge A, Hopiavuori A, Fu Z, Ward N, Clarke OB, Shen Y, Zhang Y, Hendrickson WA, Yang T. Structural and functional characterization of the bestrophin-2 anion channel. Nat Struct Mol Biol, 2020; 27(4): 382-391
- Zhang Y, Kittredge A, Ward N, Ji C, Chen S, Yang T. ATP activates bestrophin ion channels through direct interaction. Nat Commun, 2018; 9(1): 3126
- Li Y, Zhang Y, Xu Y, Kittredge A, Ward N, Chen S, Tsang SH, Yang T. Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE. eLife, 2017; 6: e29914
- Yang T, Hendrickson WA, Colecraft HM. Preassociated apocalmodulin mediates Ca2+-dependent sensitization of activation and inactivation of TMEM16A/16B Ca2+-gated Cl- channels. PNAS, 2014; 111(51): 18213-8
- Yang T, Liu Q, Kloss B, Bruni R, Kalathur RC, Guo Y, Kloppmann E, Rost B, Colecraft HM, Hendrickson WA. Structure and selectivity in bestrophin ion channels. Science, 2014; 346(6207): 355-9
- Yang T, He LL, Chen M, Fang K, Colecraft HM. Bio-inspired voltage-dependent calcium channel blockers. Nat Commun, 2013; 4: 2540
- Yang T, Suhail Y, Dalton S, Kernan T, Colecraft HM. Genetically encoded molecules for inducibly inactivating CaV channels. Nat Chem Biol, 2007; 3(12):795-804
For a complete list of publications, please visit PubMed.gov