Tingting Yang, PhD

Our Providers

Academic Appointments

  • Assistant Professor of Ophthalmic Sciences (in Ophthalmology)
Tingting Yang, PhD

Our laboratory studies the structure, function and regulation of a family of calcium (Ca2+)-activated chloride (Cl-) channels named bestrophins, and the pathological mechanisms and treatment of their associated diseases. 

Bestrophins 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 homolog 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     

NIH Grants

  • THERAPEUTIC GENE EDITING AND MULTIMODAL IMAGING IN JUVENILE MACULAR DEGENERATION (Federal Gov)

    Jun 1 2020 - May 31 2025

    MECHANISTIC CHARACTERIZATION OF CALCIUM-ACTIVATED CHLORIDE CHANNELS IN RETINAL PIGMENT EPITHELIUM (Federal Gov)

    Sep 1 2019 - Mar 31 2023

    MECHANISTIC CHARACTERIZATION OF CALCIUM-ACTIVATED CHLORIDE CHANNELS IN RETINAL PIGMENT EPITHELIUM (Federal Gov)

    Sep 1 2019 - Mar 31 2023

    STRUCTURE-FUNCTION ANALYSIS OF BESTROPHINS (Federal Gov)

    May 1 2015 - Apr 30 2017

    NEW YORK STRUCTURAL BIOLOGY CENTER (Private)

    Aug 1 2010 - Jul 31 2015

    RESEARCH AGREEMENT WITH BROOKHAVEN NATIONAL LABS (Federal Gov)

    Feb 1 2009 - Jan 31 2014

    MOLECULAR DETERMINANTS OF L-TYPE CALCIUM CHANNEL GATING (Federal Gov)

    Apr 15 2002 - Jun 30 2013

Publications

Owji AP, Kittredge A, Zhang Y, Yang T. Structure and Function of the Bestrophin family of calcium-activated chloride channels. Channels (Austin), 2021; 15(1): 604-623

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

Kittredge A, Zhang Y, Yang T. Evaluating BEST1 mutations in hPSC-RPE cells. Methods Enzymol, 2021; 654: 365-382

Wu J, Venkata Subbaiah KC, Jiang F, Hedaya O, Mohan A, Yang T, Welle K, Ghaemmaghami S, Tang WHW, Small E, Yan C, Yao P. MicroRNA-574 regulates FAM210A expression and influences pathological cardiac remodeling. EMBO Mol Med, 2021; 13(2): e12710

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

Lima de Carvalho JR Jr, Kim HJ, Ueda K, Zhao J, Owji AP, Yang T, Tsang SH, Sparrow JR. Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice. J Biol Chem, 2020; 295(19): 6767-6780

Ji C, Li Y, Kittredge A, Hopiavuori A, Ward N, Yao P, Fukuda Y, Zhang Y, Tsang SH, Yang T. Investigation and restoration of BEST1 activity in patient-derived RPEs with dominant mutations. Sci Rep, 2019; 9(1):19026

Ji C, Kittredge A, Hopiavuori A, Ward N, Chen S, Fukuda Y, Zhang Y, Yang T. Dual Ca2+-dependent gates in human Bestrophin1 underlie novel disease-causing mechanisms of gain-of-function mutations. Commun Biol, 2019; 2:240

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

Kittredge A, Ji C, Zhang Y, Yang T. Differentiation, maintenance and analysis of human retinal pigment epithelium cells: a disease-in-a-dish model for BEST1 mutations. J Vis Exp, 2018; (138): 57791

Kittredge A, Ward N, Hopiavuori A, Zhang Y, Yang T. Expression and purification of mammalian Bestrophin ion channels. J Vis Exp, 2018; (138): 57832

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, Colecraft HM. Calmodulin regulation of TMEM16A and 16B Ca2+-activated chloride channels. Channels, 2016; 10(1): 38-44

Yang T, Justus S, and Li Y, Tsang SH. BEST1: the best target for gene and cell therapies. Molecular Therapy, 2015; 23(12): 1805-9

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 (#corresponding authors)

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, Colecraft HM. Regulation of voltage-dependent calcium channels by RGK proteins. Biochim Biophys Acta, 2013; 1828(7):1644-54

Yang T, He LL, Chen M, Fang K, Colecraft HM. Bio-inspired voltage-dependent calcium channel blockers. Nat Commun, 2013; 4: 2540

Yang T#, Puckerin A, Colecraft HM#. Distinct RGK GTPases differentially use α1- and auxiliary β- binding-dependent mechanisms to inhibit CaV1.2/CaV2.2 channels. PLoS One, 2012; 7(5):e37079 (#corresponding authors)

Yang T, Xu X, Kernan T, Wu V, Colecraft HM. Rem, a member of the RGK GTPases, inhibits recombinant CaV1.2 channels using multiple mechanisms that require distinct conformations of the GTPase. J physiol, 2010; 588(Pt 10):1665-1681 (Cover Article)

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 (Faculty of 1000 selection)

For a complete list of publications, please visit PubMed.gov