 | Mark Trifiro, M.D. Div. of Endocrinology and Metabolism Lady Davis Institute for Medical Research SMBD-Jewish General Hospital Tel: (514) 340-8260 Ext 5269 mark.trifiro [at] mcgill.ca (Email) |
Research:
The human androgen receptor (AR) is a member of the nuclear receptor superfamily, but has several exclusive attributes: 1) loss-of and gain-of-function mutations, each with their definitive clinical syndromes; 2) a functional polyglutamine (polyGln) tract polymorphism that modulates AR transactivation; and 3) somatic genomic instability of the AR CAG repeat with its unique impact on androgen physiology. We have made significant contributions to each research area and continue to investigate these distinctive properties to further gain a clearer understanding of AR action in both normal and diseased states.
The AR functions primarily as a steroid-activated transcription factor and is a critical signaling molecule involved in numerous cellular functions pertaining to the development and growth of the male sexual and reproductive systems. Androgen insensitivity syndromes (AIS) are inheritable human disorders where a graded loss-of-function of the single X-linked AR allele is correlated with sexual development abnormalities in XY individuals: complete (female phenotype), partial (male/female ambiguous), or mild (male phenotype). Our extensive structure-function analyses of AR mutants, in conjunction with novel molecular dynamic simulation (MDS) studies, have helped us characterize the molecular details of AR mechanism of action.
Another class of AR gene mutation, a so-called trinucleotide repeat expansion, occurs when the normally polymorphic CAG repeat that encodes the polyGln tract is expanded past a pathologic threshold. Men who inherit an AR gene with more than 37 CAGs develop a late-onset neurological disorder termed spinobulbar muscular atrophy (SBMA). Various pathways may be involved in SBMA pathogenesis; we are investigating whether misregulation of the ubiquitin proteasome system for protein degradation (UPS) plays a role in expanded polyGln-mediated neuronal dysfunction.
The AR also plays a central role both in the initial androgen-dependent and later androgen-independent stages of prostate cancer (CaP). Somatic gain-of-function AR mutations can create hyperactive, promiscuous, subversive or ligand-independent active ARs. By documenting somatic AR CAG repeat contractions in normal prostate and CaP cells, we have discovered a hitherto unrecognized aspect of androgen action. CAG repeat instability creates widespread heterogeneity of ARs in androgen-sensitive organs and, because CAG repeat length influences AR function, potential selection and paracrine processes can ensue that can contribute to multiple disease processes. Prostate diseases may simply be somatic AR disorders reflecting CAG repeat instability. To investigate this aspect of AR function, we are generating knock-in mice with genetically stable or unstable sequences coding for glutamine tracts of different lengths. We are also interested in developing AR-targeting compounds that could be used in the treatment of prostate cancer.
Finally, we have successfully introduced novel methodology for developing a reagentless biosensing device for glucose recognition. To completely control blood glucose and reduce hypoglycemia episodes in diabetic patients, a more accurate and continuous monitoring of glucose is needed. A 鈥渃losed loop system鈥� where constant glucose measurements will dictate appropriate insulin and/or glucagon delivery would alleviate many of the problems associated with "tight control". In conjunction with our collaborators from 91社区 and Concordia, our goal is to further optimize this novel glucosensor technology.
Selected Publications:
Mandrusiak LM, Beitel LK, Wang X, Scanlon TC, Chevalier-Larsen E, Merry DE, Trifiro M. Transglutaminase potentiates ligand-dependent proteasome dysfunction induced by polyglutamine-expanded androgen receptor. Hum Mol Genet, 13: 1497-1506, 2003.
Gottlieb B, Beitel LK, Wu JH, Trifiro M. The Androgen Receptor Gene Mutations Database: 2004 Update. Hum Mutat, 23: 527-523, 2004. [Erratum Hum Mutat 24: 102, 2004.
Elhaji YA, Wu JH, Gottlieb B, Beitel LK, Alvarado C, Batist G, Trifiro M. An examination of how different mutations at arginine 855 of the androgen receptor result in different androgen insensitivity phenotypes. Mol Endocrinol 18: 1876-1886, 2004.
Gottlieb B, Beitel LK, Trifiro MA. The molecular pathology of the androgen receptor in male (in)fertility. Reprod BioMed Online 10: 42-48, 2005 ().
Beitel LK, Scanlon T, Gottlieb B, Trifiro M. Progress in spinobulbar muscular atrophy research: Insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor. Neurotoxicity Res 7: 219-230, 2005.
Alvarado C, Beitel LK, Sircar K, Aprikian A, Gottlieb B, Trifiro M. Somatic mosaicism and cancer: A micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res 65: 8514-8518, 2005.
Elhaji YA, Stoica I, Dennis S, Purisima EO, Lumbroso R, Beitel LK, Trifiro MA. Impaired helix 12 dynamics due to proline 892 substitutions in the androgen receptor are associated with complete androgen insensitivity. Hum Mol Genet 15: 921-931, 2006. [Corrigendum Hum Mol Genet 15: 561, 2006]
Sircar K, Gottlieb B, Alvarado C, Aprikian A, Beitel LK, Alam-Fahmy M, B茅gin L, Trifiro M. Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues. Prostate Cancer Prostatic Dis (in press) 2007. [2007 Apr 17; Epub ahead of print]
Gottlieb B, Beitel LK, Trifiro MA. Will knowledge of human genome variation result in changing cancer paradigms? BioEssays 29: 678-685, 2007.
Di Fabio F, Alvarado C, Majdan A, Gologan A, Voda L, Mitmaker E, Beitel LK, Gordon PH, Trifiro M. Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression. J Gastrointest Surg 11: 1521-1528, 2007.