Pre receptor steroid metabolism, Sulphation and steroid hormone metabolism, translational steroid physiology, healthy aging, intracellular trafficking.
The conjugation of a sulphate group (sulphation) to small molecules has an integral and essential role in living organisms. In mammalian physiology, the sulphation system is important for detoxifying drugs, food additives, and toxins from intestinal bacteria or the environment. In humans, defects to the sulphation pathway result in a broad range of clinical phenotypes ranging from neurological disorders, severe bone phenotypes and disorders of androgen synthesis. Critically, sulphation is dependent upon provision of the universal sulphate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) by PAPS synthase (PAPSS).
Dr Dhir’s research focuses primarily on the involvement of the sulphation pathway in regulating sex steroids such as Dehydroepiandrosterone (DHEA) synthesised in the adrenal gland. Vivek has a major interest in the molecular mechanisms by which PAPSS regulates sulphation and to examine underlying cellular events that control conversion of DHEA to its sulphate ester DHEAS. The aim is to establish a link between these mechanisms and the clinical manifestations observed in patients with disorders related to deficiencies in sulphation. This work will be extended to study the links between these deficiencies and drug detoxification in the liver in which sulphation plays an important role.
Intracellular movement of steroids is of great interest since defects in such processes can be linked to clinical manifestation of hormone disease. Dr Dhir is interested in studying the intracellular movement of steroid hormones with the aim to identify the important components of the cellular trafficking machinery that are required for hormone function. In particular, Vivek works alongside physicists to develop powerful microscopy based tools for such studies.
Idkowiak J, Lavery GG, Dhir V, Barrett TG, Stewart PM, Krone N, Arlt W. Premature adrenarche: novel lessons from early onset androgen excess. Eur J Endocrinol. 2011 Aug;165(2):189-207
Idkowiak J, Malunowicz EM, Dhir V, Reisch N, Szarras-Czapnik M, Holmes DM, Shackleton CHL, Davies JD, Hughes IA, Krone N and Arlt W. Concomitant mutations in the P450 oxidoreductase and androgen receptor 2 genes presenting with 46,XY disordered sex development and androgenization at adrenarcheJ Clin Endocrinol Metab 2010 Jul;95(7):3418-27
Parajes S, Loidi L, Reisch N, Dhir V, Rose IT, Hampel R, Quinkler M, Conway GS, Castro-Feijóo L, Araujo-Vilar D, Pombo M, Dominguez F, Cole TR, Kirk JM, Kaminsky E, Rumsby G, Arlt W, Krone N. Functional Consequences of Seven Novel Mutations in the CYP11B1 Gene - Four Mutations Associated with Non-Classic and Three Mutations Causing Classic 11β-Hydroxylase Deficiency. J Clin Endocrinol Metab. 2010 Feb;95(2):779-88. 2010 Feb;95(2):779-88
Dhir V, Noordam C, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL, Arlt W. Inactivating PAPSS2 Mutations in a Patient with Premature Pubarche. N Engl J Med. 2009, 360(22):2310-8
Dhir V, Reisch N, Bleicken CM, Lebl J, Kamrath C, Schwarz H, Grotzinger J, Sippell WG, Riepe FG, Arlt W, Krone N. Steroid 17α Hydroxylase deficiency: Functional Characterization of four mutants (A174E, V178D, R440C, L465P) in the CYP17A1 gene. J Clin Endocrinol Metab. 2009, 94(8):3058-64
Bleicken C, Loidi L, Dhir V, Parajes S, Quinteiro C, Dominguez F, Grötzinger J, SippellGW, RiepeFG, ArltW and Krone N. Functional characterization of three CYP21A2 sequence variants (p.A265V, p.W302S, p.D322G) employing a yeast co-expression system.. Hum Mutat. 2009, 30(2):E443-50.
Dhir V, Ivison HE, Krone N, Shackleton CH, Doherty AJ, Stewart PM and Arlt W. Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P. Mol Endocrinol. 2007, 21(8):1958-68
Plumb DA, Dhir V, Mironov A, Ferrara L, Poulsom R, Kadler KE, Thornton DJ, Briggs MD, Boot-Handford RP. Collagen XXVII is developmentally regulated and forms thin fibrillar structures distinct from those of classical vertebrate fibrillar collagens. J Biol Chem. 2007, 282(17):12791-5.