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Harris, Thurl

Thurl Harris

Primary Appointment

Pharmacology

Contact Information

PO Box 800735
Charlottesville, VA 22908
Telephone: 434-924-1584
Fax: 434-982-3878
Email: teh3c@virginia.edu
Website: https://pharm.virginia.edu/harris/sample-page/

Research Interests

Molecular mechanisms controlling insulin signaling and fat synthesis.

Research Description

As Paleolithic hunter gatherers, the human diet was relatively low in fats and simple carbohydrates. Technological advances, beginning with the agricultural revolution 12,000 years ago and culminating with the mechanization of food production in the last century, have provided a significant portion of the world?s population with access to inexpensive, energy-dense food. In the modern age the ready availability of carbohydrates and fats, combined with a large reduction in physical labor, has led to a predictable rise in obesity. The Center for Disease Control estimates currently 34% of the U.S. population is characterized as overweight (B.M.I. of 25-30), and another 41% are obese (B.M.I.>30), giving an astonishing 3 out 4 Americans defined as overweight or obese. As an underlying risk factor for type II diabetes and cardiovascular disease, understanding how obesity promotes the development of these diseases is of extreme importance for worldwide health. Food intake triggers the release of insulin, an anabolic hormone that promotes nutrient storage and protein synthesis. Our laboratory is interested in the mechanisms underlying the storage and release of carbohydrates and fats as triacylglycerol (TAG) in adipose tissue, and the dysregulation of insulin signaling that occurs during obesity. The mTOR Signaling Pathway - A key player in the insulin signaling cascade is the mammalian target of rapamycin (mTOR), a highly conserved Ser-Thr phosphatidylinositol 3-kinase-related protein kinase that integrates cellular energy status and growth factors to regulate cellular growth, survival, and metabolism. mTOR forms two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) each of which catalyzes the phosphorylation of different substrates in response to insulin. Under conditions of caloric excess, such as that seen during diet-induced obesity, both arms of the mTOR pathway can be affected. We study the molecular mechanisms of how insulin signaling activates the two different mTOR complexes, the targets of mTORC1 and 2, and the functional consequences of obesity on mTOR activity. Triacylglycerol Storage in Adipocytes and Inflammation - Another important research interest in the laboratory are the enzymatic pathways by which adipocytes store fatty acids as TAG and release fatty acids for energy between meals. It is clear that obesity results in dysregulation of the storage and breakdown of TAG in adipose tissue and genetic studies in mice have suggested that improper regulation of this process can cause peripheral insulin resistance and glucose intolerance- both hallmarks of the pre-diabetes. We study the molecular alterations in TAG homeostasis in adipocytes and how this can impact the physiology of whole body metabolism.

Selected Publications

Hennessy M, Granade ME, Hassaninasab A, Wang D, Kwiatek JM, Han GS, Harris TE, Carman GM, Casein kinase II-mediated phosphorylation of lipin 1? phosphatidate phosphatase at Ser-285 and Ser-287 regulates its interaction with 14-3-3? protein., 2019; The Journal of biological chemistry. 294(7) 2365-2374 PMID: 30617183 | PMCID: PMC6378963

Ahern KW, Serbulea V, Wingrove CL, Palas ZT, Leitinger N, Harris TE, Regioisomer-independent quantification of fatty acid oxidation products by HPLC-ESI-MS/MS analysis of sodium adducts., 2019; Scientific reports. 9(1) 11197 PMID: 31371760 | PMCID: PMC6671977

Granade ME, Harris TE, Purification of Lipin and Measurement of Phosphatidic Acid Phosphatase Activity from Liposomes., 2018; Methods in enzymology. 607() 373-388 PMID: 30149866 |

Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna BD, Neal BP, Boroda S, Li M, Brenneman B, Abounader R, Floyd D, Lee J, Nakano I, Godlewski J, Bronisz A, Sulman EP, Mayo M, Gioeli D, Weber M, Harris TE, Purow B, Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha., 2017; Neuro-oncology. () PMID: 29048560 | PMCID: PMC5777487

Boroda S, Takkellapati S, Lawrence RT, Entwisle SW, Pearson JM, Granade ME, Mullins GR, Eaton JM, Vill?n J, Harris TE, The Phosphatidic Acid-Binding, Polybasic Domain is Responsible for the Differences in the Phosphoregulation of Lipins 1 and 3., 2017; The Journal of biological chemistry. () PMID: 28982975 |

Boroda S, Niccum M, Raje V, Purow BW, Harris TE, Dual activities of ritanserin and R59022 as DGK? inhibitors and serotonin receptor antagonists., 2016; Biochemical pharmacology. 123() 29-39 PMID: 27974147 | PMCID: PMC5164959

Adamson SE, Griffiths R, Moravec R, Senthivinayagam S, Montgomery G, Chen W, Han J, Sharma PR, Mullins GR, Gorski SA, Cooper JA, Kadl A, Enfield K, Braciale TJ, Harris TE, Leitinger N, Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation., 2016; The Journal of clinical investigation. 126(4) 1311-22 PMID: 26927671 | PMCID: PMC4811113

Mullins GarrettR., Wang Lifu, Raje Vidisha, Sherwood SamanthaG., Grande RebeccaC., Boroda Salome, Eaton JamesM., Blancquaert Sarah, Roger PierreP., Leitinger Norbert, Harris ThurlE., Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes., ; Proceedings of the National Academy of Sciences of the United States of America. 111(49) 17450-5 | PMCID: 25422441

Eaton JM, Takkellapati S, Lawrence RT, McQueeney KE, Boroda S, Mullins GR, Sherwood SG, Finck BN, Vill?n J, Harris TE, Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation., 2014; The Journal of biological chemistry. 289(26) 18055-66 PMID: 24811178 | PMCID: PMC4140300

Creutz CE, Eaton JM, Harris TE, Assembly of high molecular weight complexes of lipin on a supported lipid bilayer observed by atomic force microscopy., 2013; Biochemistry. 52(30) 5092-102 PMID: 23862673 | PMCID: PMC4041088

Dominguez CL, Floyd DH, Xiao A, Mullins GR, Kefas BA, Xin W, Yacur MN, Abounader R, Lee JK, Wilson GM, Harris TE, Purow BW, Diacylglycerol kinase ? is a critical signaling node and novel therapeutic target in glioblastoma and other cancers., 2013; Cancer discovery. 3(7) 782-97 PMID: 23558954 | PMCID: PMC3710531

Eaton JM, Mullins GR, Brindley DN, Harris TE, Phosphorylation of lipin 1 and charge on the phosphatidic acid head group control its phosphatidic acid phosphatase activity and membrane association., 2013; The Journal of biological chemistry. 288(14) 9933-45 PMID: 23426360 | PMCID: PMC3617293

Zhang C, Wendel AA, Keogh MR, Harris TE, Chen J, Coleman RA, Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling., 2012; Proceedings of the National Academy of Sciences of the United States of America. 109(5) 1667-72 PMID: 22307628 | PMCID: PMC3277174

Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM, mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway., 2011; Cell. 146(3) 408-20 PMID: 21816276 | PMCID: PMC3336367

Liu GH, Qu J, Carmack AE, Kim HB, Chen C, Ren H, Morris AJ, Finck BN, Harris TE, Lipin proteins form homo- and hetero-oligomers., 2010; The Biochemical journal. 432(1) 65-76 PMID: 20735359 | PMCID: PMC3117669

Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE, Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism., 2010; Diabetes. 59(6) 1397-406 PMID: 20332342 | PMCID: PMC2874700

Kim HB, Kumar A, Wang L, Liu GH, Keller SR, Lawrence JC, Finck BN, Harris TE, Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors., 2010; Molecular and cellular biology. 30(12) 3126-39 PMID: 20385772 | PMCID: PMC2876672