Medical Student Research Fellowship for Summer 2005

Mentor: David Mangelsdorf, Ph.D.
Department: Pharmacology
Room number: L3.110B
Mail Code: 9050
Phone number: 86349
E-mail: davo@mango.utsouthwestern.edu
Project title: There are two potential projects: 1) The Role of LXRs in Skin; 2) The role of Vitamin D in Adipogenesis

Human subjects IRB approved project number (where applicable): n/a

Animal subjects IRB approved project number (where applicable): APN 0693-04-02-01

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Both projects are animal-based research

Brief Description of Project:

The first project proposes to look at the regulation of 5 alpha-reductase Type II (5alphaRed) by the oxysterol receptors (LXRs) in skin. 5alphaRed is the enzyme that converts testosterone into DHT, the active androgen in skin that is responsible for hair loss. We have recently found LXRs repress this enzyme's expression, suggesting it may be an important therapeutic target for androgenic alopecia.

The second project focuses on the role of Vitamin D in adipogenesis. We have recently found that Vitamin D is important for normal fat development and deposition; and we are exploring its mechanism of action.

The third project focuses on identifying the polymorphism in the FXR gene (which encodes the bile acid receptor) that is responsible for predisposing animals, and possibly humans, to cholesterol gallstone disease.

Previous Research Activities or Publications with Medical Students:

Lu, T.T., Makishima, M., Repa, J.J., Schoonjans, K., Kerr, T.A., Auwerx, J., and Mangelsdorf, D.J. (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molecular Cell 6: 507-515.

Lobaccaro, J.-M.A., Repa, J.J., Lu, T.T., Caira, F., Henry-Berger,J., Volle, D.H., and Mangelsdorf, D.J. (2001) Regulation of lipid metabolism by the orphan receptors. Ann.Endocrinol. 62(3): 239-247.

Lu, T.T., Makishima, M., Repa, J.J. and Mangelsdorf, D.J. (2001) Adolf Windaus Prize lecture: Nuclear orphan receptor regulation of cholesterol and bile acid homeostasis. In Biology of Bile Acids in Health and Disease-Falk Symposium 120 (van Berge Henegouwen et al, ed.), Kluwer Academic Publishers, Lancaster, UK, pp. 28-36.

Lu, T.T., Repa, J.J., and Mangelsdorf, D.J. (2001) Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J.Biol.Chem., 276:37735-37738.

Makishima, M., Lu, T.T., Xie, W., Whitfield, G.K., Domoto, H., Evans, R.M., Haussler, M.R., and Mangelsdorf, D.J. (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313-1316.

Lu, T.T., Makishima, M., and Mangelsdorf, D.J. (2003) Vitamin D receptor as a bile acid sensor. In: Falk Sympsium 129 - Bile Acids: From Genomics to Disease and Therapy (G. Paumgartner, ed.) Kluwer Academic Publishers, London, UK, pp.39-45.

Cheng, J.B., Motola, D.L., Mangelsdorf, D.J., and Russell, D.W. (2003) De-orphanization of cytochrome P450 2R1: A microsomal vitamin D 25-hydroxylase. J.Biol.Chem. 278:38084-38093.

Shulman, A.I., Larson, C., Mangelsdorf, D.J. and Ranganathan, R. (2004) Molecular basis of allosteric ligand activation in RXR heterodimers. Cell 116:417-429.

Adachi, R., Shulman, A.I., Yamamoto, K., Shimomura, I., Yamada, S., Mangelsdorf, D.J., and Makishima, M. (2004) Structural determinants for vitamin D receptor response to endocrine and xenobiotic signals. Molecular Endocrinology 18:43-52.

Cheng, J.B., Levine, M.A., Bell, N.H., Mangelsdorf, D.J., and Russell, D.W. (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc. Natl. Acad. Sci. USA.,101:7711-7715.

Motola, D.L. and Mangelsdorf, D.J. (2005) Vitamin D receptor as a sensor for toxic bile acids. In: Vitamin D, Second Edition (David Feldman, ed), Elsevier Inc Publishers, San Diego, CA, Chapter 53, 863-870.

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