P. Michael Conn

In work conducted over the last five years, Conn and his team have identified an underlying biological principle that has dramatically changed scientists' understanding of cellular mutations that result in human disease. He has demonstrated that it is possible to manipulate and redirect the routing of non-functional diabetes, Alzheimer's disease and cataracts. This approach is described at http://en.wikipedia.org/wiki/pharmacoperone

It is becoming well-recognized that mutations of receptors, enzymes and ion channels frequently result in protein misfolding and subsequent retention by the cell's quality control system. Misfolding can result in protein molecules that retain intrinsic function yet become misrouted within the cell and, for reasons of mis-location only, cease to function normally and result in disease. This contrasts with the prior presumption that mutational inactivation always reflects loss of intrinsic function (i.e., a receptor that either fails to recognize ligand or does not couple productively to its effector). Recognition of this alternate concept immediately presents the therapeutic opportunity to correct misrouting and rescue mutants, thereby restoring function and, potentially, curing disease.

Pharmacoperones are small molecules that enter cells, bind specifically to misfolded mutant proteins, correct their folding, and allow them to escape retention by the cellular quality control system. They then route to the plasma membrane (or other site) where they can function normally.

In principle, the pharmacoperone rescue approach might apply to a range of human diseases that result from misfolding - among these: cyctic fibrosis, hypogonadotropic hypogonadism, nephrogenic diabetes insipidus, retinitis pigmentosa, hypercholesterolemia, cataracts, neurodegenerative diseases (Huntington's, Alzheimer's, Parkinson's). In the case of particular proteins, this approach has succeeded with a striking number of different mutants, suporting our view that pharmacoperones will become powerful ammunition in our therapeutic arsenal.

P. Michael Conn is the associate director and a senior scientistat the center, and professor of physiology and pharmacology and cell biology and development at OHSU, where he served for eleven years as special assistant to the president. After receiving a B.S. degree and teaching certificate from the University of Michigan (1971), an M.S. from North Carolina State University (1973)and a Ph.D. degree from Baylor College of Medicine (1976), Conn did a fellowship at the National Institute of Child Health and Human Development, NIH, then joined the Department of Pharmacology, Duke University Medical Center where he was promoted to Associate Professor in 1982.In 1984, he became professor and head of pharmacology at the University of Iowa College of Medicine, a position he held for eleven years.

Conn is the prior Editor-in-Chief of Endocrinology, Molecular and Cellular Neurosciences (founding editor), Methods in Neuroscience,and Recent Progress in Hormone Research, and prior editor of J. Clinical Endocrinology and Metabolism; he is presently the Editor-in-Chief of Endocrine, Methods, Contemporary Endocrinology,and Contemporary Drug Therapy. He is the editor of texts in pharmacology (Essentials of Pharmacology) neuroscience (Neuroscience inMedicine), neuroendocrinology (Neuroendocrinology in Physiology and Medicine), endocrinology (Endocrinology: Basic and Clinical Principles) and molecular endocrinology (Principles of Molecular Regulation), as well as more than 100 volumes in endocrinology and neuroscience.

Conn served on the National Board of Medical Examiners, including two years as chairman of the reproduction and endocrinology committee. Conn is best known for his research in the area of the cellular and molecular basis of action of gonadotropin releasing hormone in the pituitary and CNS. He has authored or co-authored nearly 300 publications and 130 books in this area.

The work of his laboratory has been recognized with a MERIT award from the NIH, the J.J. Abel Award of the American Society for Pharmacology and Experimental Therapeutics, and Weitzman, Oppenheimer and Ingbar Awards of the Endocrine Society, the National Science Medal of Mexico (the Miguel Aleman Prize) and the Stevenson Award of Canada. In 2004, he received the Oregon State Award for Medical Discovery (Medical Research Foundation of Oregon). His projects have been continuously funded by peer-reviewed federal support since 1976.

Conn is a previous member of Council for the American Society for Cell Biology and the Endocrine Society and is a prior President of the Endocrine Society, during which time he founded the Hormone Foundation and worked with political leadership to create much of our nation's program in diabetes. He served on the FASEB Board of Directors. Conn's students and fellows have gone on to become leaders in industry and academia. He is an elected member of the Mexican Institute of Medicine.

KEY PUBLICATIONS

Janovick, J.A., P.E. Knollman, S.P. Brothers, R. Ayala-Yanez, A.S. Aziz, and P.M. Conn, 2006. Regulation of G protein coupled receptor trafficking by inefficient plasma membrane expression: Molecular basis of an evolved strategy. J. Biol. Chem.281(13):8417-8425.

Conn, P.M., J.A. Janovick, S.P. Brothers, and P.E. Knollman. 2006. "Effective Inefficiency:" Cellular control of protein trafficking as a mechanism of posttranslational regulation. J. Endocrinol.190(1):13-16.

Janovick, J.A., S.P. Brothers, P.E. Knollman, and P.M. Conn. 2007. Specializations of a G-protein coupled receptor that appear to aid with detection of frequency modulated signals. FASEB J.

Conn, P.M., P.E. Knollman, S.P. Brothers, J.A. Janovick. 2006. Protein folding as post-translational regulation: Evolution of a mechanism for controlled plasma membrane expression of a GPCR. Mol. Endocrinol.20(12):3035-3041.

Ulloa-Aguire, A., and P.M. Conn. 2007. G-protein-coupled receptor trafficking: Understanding the chemical basis of health and disease. ACS Chem. Biol.
1(10):631-638.

Conn PM, Ulloa-Aguirre A, Ito J, Janovick JA. G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol. Rev.59(3):225-250, 2007. PMID: 17878512.

Ulloa-Aguirre A, Janovick JA, Miranda AL, Conn PM. G protein-coupled receptor trafficking: understanding the chemical basis of health and disease. ACS Chem. Biol. 1(10):631-638,2006. PMID: 17168568.

Knollman PE and Conn PM. Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor. (Epub 2008 May 27) Arch. Biochem. Biophys. 477(1):92-97, 2008. NIHMSID: 66219. PMID: 18541137.

Conn PM, Parker JV. Winners and losers in the animal research war. American Scientist96(3):184-186, 2008. http://www.americanscientist.org/issues/pub/winners-and-losers-in-the-animal-research-wars/

Conn PM, Parker JV. The animal research war. FASEBJ. 22(5):1294-1295, 2008. http://www.fasebj.org/cgi/content/full/22/5/1294. PMID: 18450645.

Conn PM, Parker JV. The T-Word. The Scientific American.2009 (In press).

JanovickJA, Maya-NunezG, Ulloa-AguirreA, JiT, HuhtaniemiIT, DiasJA, VerbostP, ConnPM. Increased plasma membrane expression of hFSHR by a small molecule Thienopyr(Im)Idine. In press, 2008.

JanovickJA, PatneyA, MoselyR, GouletM, AltmanM, RushT, Cornea A,Conn PM. Biochemical mechanism of action of pharmacoperones in rescue of misfolded G-protein coupled receptor mutants. In press, 2008.

BOOKS

1. Conn, P.M. and Parker, J.S. The Animal Research War. (2008). Macmillan/Palgrave ISBN-10: 023060014X ISBN-13: 978-0230600140.

2. Conn, P.M. Sourcebook of Models for Biomedical Research, Humana Press, (2008). ISBN13: 978-1-58829-933-8; ISBN10: 978-1-58829-933-3.

3. Conn, P.M. Neuroscience in Medicine, Springer, Totowa, NJ third edition (2008)

4. Jennes, L, Traurig, H, Brueckner J.K. and Conn, P.M. Atlas of the Human Brain (on CD), Springer, 2008.

To see a full listing of Dr.  Conn's publications click here