Ta Yuan Chang
Dartmouth College
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Primary Section: 42, Medical Physiology and Metabolism Secondary Section: 21, Biochemistry Membership Type:
Member
(elected 2021)
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Biosketch
Dr. T.Y. Chang is a biochemist and somatic cell geneticist. In Dr. Chang's laboratory, work led to the discovery of four novel CHO cell mutants, unveiling four new genes vital to cholesterol metabolism:
M1/M19 (1978, 1994): Mutant M19 was crucial in human genomic DNA transfection, revealing the S2P gene responsible for the second SREBP processing enzyme at the Golgi. The discovery of S2P was made in collaboration with the Brown and Goldstein Lab in 1997.
25RA (1980): DNA samples from 25RA cells were instrumental in identifying a dominant gain-of-function mutant form of the SCAP gene (1996), a key player in the sterol-dependent SREBP pathway, controlling gene expressions of cholesterol and fatty acid biosynthetic enzymes. The SCAP gene was identified in the Brown and Goldstein Lab in 1996.
CT60 (1990): CT60, used for human genomic DNA transfection in the Pentchev lab at NIH, led to the identification of the NPC1 gene (1997), essential for endosomal cholesterol export. Mutations in NPC1 gene cause the often-fatal pediatric neurological disease, NPCD.
AC29 (1988): AC29 mutant was another recipient of human genomic DNA transfections and led to the identification of the acyl-CoA: cholesterol acyltransferase 1 (ACAT1/SOAT1) gene, accomplished in the Chang Lab in 1993. ACAT1 encodes the primary cholesterol storage enzyme across all body cells and is the first member of the membrane-bound O-acyltransferases (MBOATs) family. Identifying the ACAT1 gene laid the foundation for ACAT1-related research, emphasizing its role in regulating cholesterol homeostasis, with implications for diseases like Alzheimer's disease and NPCD.
Research Interests
The Chang lab, with T.Y. as the PI and Catherine as the co-I, studies cholesterol homeostasis in the central nervous system and in systemic tissues, with a focus on investigating the biochemistry and physiological roles of the cholesterol storage enzyme acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), named as sterol O-acyltransferase 1 (SOAT1) in GenBank.
ACAT1 is a membrane bound protein in the endoplasmic reticulum. It plays a key role in the cholesterol storage process. Our laboratory discovered the Acat1/Soat1 gene. In many neurodegenerative diseases, cholesterol dys-homeostasis occur; in addition, the cholesterol-rich membrane microdomains in various neuronal cell types are damaged. We showed that, in mouse models for Alzheimer’s disease (AD) and for Niemann Pick type C disease (NPCD), blocking cholesterol storage by inactivating the Acat1 gene can divert the cholesterol storage pool, such that the “mobilized“ cholesterol facilitates cholesterol homeostasis and repairs the damaged membrane microdomains. Current and future investigations are directed to develop brain-permeable ACAT inhibitors, to investigate the consequences of inhibiting ACAT in cells, and to elucidate the biochemical mechanism that governs sterol-specific activation of ACAT in vitro.
