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David Lawrence Silver

Professor

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Contact: 66012172

Dr. Silver is Professor and Deputy Director in the Signature Research Program in Cardiovascular & Metabolic Disorders at the Duke-NUS Medical School.  Dr. Silver obtained his Ph.D. in Genetics from Michigan State University, and postdoctoral training at Columbia University specializing in biochemistry and lipid metabolism. His long-standing research interests are in the areas of lipid storage, transport and metabolism and has a translational focus in applying his laboratory’s discoveries to the treatment of human diseases.  Dr. Silver’s laboratory is supported through competitive grants from the National Medical Research Council, Ministry of Education and National Research Foundation, is multidisciplinary utilizing biochemistry, structural biology, molecular genetics in mice and humans, and molecular and cellular biology. Dr. Silver’s notable discoveries include the FITM family of endoplasmic reticulum proteins and Mfsd2a, a lysolipid transporter critical for human brain growth. His laboratory’s research has been published in scientific journals such as Nature, Nature Genetics, Journal of Clinical Investigation, and Proceedings of the National Academy of Sciences, USA. Dr. Silver is the scientific founder of Vanteres and Travecta Therapeutics.

The overriding theme of our research group is to determine the molecular mechanisms by which organisms regulate lipid metabolism. This research theme is widely relevant to metabolic, immunological and neurological diseases.

Our primary interest involves the study of the transporter Mfsd2a that our laboratory discovered to be a lysophosphatidylcholine (LPC) transporter required for human brain growth and function.  LPCs are synthesized by the liver.  We showed that Mfsd2a is expressed at the blood-brain barrier and retinal-blood barriers and is required for the uptake of essential fatty acids carried by LPCs. Some of our goals are to determine how Mfsd2a achieves substrate specificity and determine the physiological roles of LPCs in brain growth and function with the aim of developing novel therapeutic agents.

Our laboratory is mechanistically driven using molecular biology, biochemistry, structural biology, metabolomics (mass spectrometry), mouse gene-targeted and transgenic models, as well as in vitro cell culture models to carry out our goals. Students and research fellows working in the lab can expect to acquire skills in molecular biology, protein biochemistry, lipid biochemistry, in vitro cell culture assays, and in physiological and biochemical analysis of genetically engineered mice.

1. Long N. Nguyen, Dongliang Ma, Guanghou Shui, Peiyan Wong, Amaury Cazenave Gassiot, Xiaodong Zhang,, Markus R. Wenk, Eyleen L.K. Goh, and David L. Silver. (2014). Mfsd2a is a transporter for the essential omega-3 fatty acid DHA. Nature, May 14, 2014.

2. Alicia Guemez-Gamboa*, Long N. Nguyen*, Hongbo Yang*, Maha S. Zaki, Majdi Kara, Tawfeg Ben-Omran, Naiara Akizu1, Rasim Ozgur Rosti, Basak Rosti, Eric Scott, Jana Schroth, Brett Copeland, Amaury Cazenave-Gassiot, Debra Q.Y. Quek, Bernice H. Wong, Bryan C. Tan, Markus R. Wenk, Murat Gunel, Stacey Gabriel, Neil C. Chi, David L. Silver¶, Joseph G. Gleeson¶   (2015) Inactivating Mutations in MFSD2A, Required for Omega-3 Fatty Acid Transport in Brain, Result in a Lethal Microcephaly Syndrome.  Nature Genetics, In Press.  ¶co-corresponding authors. * co-first authors 

3. Vafa Alakbarzade*, Abdul Hameed*, Debra Q.Y. Quek*, Barry A. Chioza*, Emma L. Baple*, Amaury Cazenave-Gassiot, Long N. Nguyen, Markus R. Wenk, Arshia Q. Ahmad, Ajith Sreekantan-Nair, Michael N. Weedon, Michael.A. Patton, Thomas T. Warner, David L. Silver¶, Andrew H. Crosby¶. (2015) A Partially Inactivating Mutation in the Blood-Brain Barrier Sodium-Dependent Lysophosphatidylcholine Transporter, MFSD2A Results in a Severe, Non-lethal Microcephaly Syndrome. Nature Genetics, In Press.  ¶co-corresponding authors. * co-first authors

4. Quek DQ, Nguyen LN, Fan H, Silver DL. (2016). Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter Mfsd2a. J Biol Chem. 2016 Mar 4. pii: jbc.M116.721035.

5. Bernice H. Wong, Jia Pei Chan, Amaury Cazenave-Gassiot, Rebecca W. Poh, Juat Chin Foo, Dwight L. A. Galam, Sujoy Ghosh, Long N. Nguyen, Veluchamy A. Barathi, Yeo S.Wey, Chi D. Luu, Markus R. Wenk, David L. Silver (2016). Mfsd2a is a transporter for the essential omega-3 fatty acid DHA in eye and important for photoreceptor cell development J. Biol. Chem. jbc.M116.721340. First Published on March 22, 2016

6. Ahmed MY, Al-Khayat A, Al-Murshedi F, Al-Futaisi A, Chioza BA, Pedro Fernandez-Murray J, Self JE, Salter CG, Harlalka GV, Rawlins LE, Al-Zuhaibi S, Al-Azri F, Al-Rashdi F, Cazenave-Gassiot A, Wenk MR, Al-Salmi F, Patton MA, Silver DL, Baple EL, McMaster CR, Crosby AH. A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. Brain. 2017 Jan 3. pii: aww318. doi: 10.1093/brain/aww318.

7. Miranda DA, Krause WC, Cazenave-Gassiot A, Suzawa M, Escusa H, Foo JC, Shihadih DS, Stahl A, Fitch M, Nyangau E, Hellerstein M, Wenk MR, Silver DL, Ingraham HA.LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity. JCI Insight. 2018 Mar 8;3(5)

8. Tamar Harel*, Debra Q. Y. Quek, Bernice H. Wong, Amaury Cazenave-Gassiot, Markus R. Wenk, Hao Fan, Itai Berger, Dorit Shmueli, Avraham Shaag, David L. Silver*, Orly Elpeleg & Shimon Edvardson. Homozygous mutation in MFSD2A, encoding a lysolipid transporte for docosahexanoic acid, is associated with microcephaly and hypomyelination Neurogenetics. 2018 Jul 24. doi: 10.1007/s10048-018-0556-6. * co-corresponding authors

9. Jia Pei Chan, Bernice H. Wong, Cheen Fei Chin, Dwight L.A. Galam, Juat Chin Foo, Sujoy Ghosh, Markus R. Wenk, Amaury Cazenave-Gassiot, and David L. Silver.  The Lysolipid Omega-3 Fatty Acid Transporter Mfsd2a Regulates Lipogenesis in the Developing Brain. PLoS Biol. 2018 Aug 3;16(8):e2006443.