Lipinski, Robert (Rob) - Date Last Updated: 05/01/2008

Rob Lipinski
PhD Candidate - Started 2002
Native of Milwaukee, WI
Lab of Wade Bushman, PhD, MD

Contact Information
Email: Rob Lipinski
President of METC Student Liaison Committee (2006-07)

Undergraduate Work
University of Wisconsin, Madison, WI (1998-2002)
Bachelors of Science, Biology (2002)

Research as of August 2006
Hedgehog signaling is necessary for the proper development of a large number of vertebrate structures and disruptions in hedgehog signaling during embryonic development causes a range of defects of the forebrain and face termed holoprosencephaly (HPE). Cyclopamine, a plant steroidal alkaloid that antagonizes Hh signaling, causes HPE in livestock and laboratory animal models. In the human population, single-allele mutations in Shh and Gli2 are associated with familial and sporadic HPE, however, there is a wide phenotypic spectrum where some carriers are severely affected and some are clinically normal. The etiology of human HPE is largely unknown.

Using cell-based assays, we have identified several dietary alkaloids,
structurally similar to cyclopamine, as weak inhibitors of Hh signaling.
Recently, several high throughput screens of synthetic small molecules
have identified various other potent Hh antagonists that are not structurally similar to cyclopamine. Using a similar approach, we have developed a high throughput cell-based assay that will be used to screen over 4,500 compounds including currently marketed pharmaceuticals, natural products, and pesticides.

We have also established a highly tractable model of holoprosencephaly in our laboratory. This model, developed by Nagase et al., in 2005, utilizes mouse whole embryo culture, where embryos are grown in vitro from embryonic day 8.5 to 10.5; the stage of embryogenesis most vulnerable to teratogenic insults. We found that mouse embryos cultured in vitro with cyclopamine demonstrate a dose-dependent reduction in expansion of the frontonasal prominence; an embryonic phenotype of holoprosencephaly. Moving forward, we will utilize this model to test the teratogenic potential of the identified dietary Hh signaling inhibitors, as well as lead compounds identified by small molecule screening. Using transgenic mice, we will then test whether single allele LOF mutations in Shh and Gli2 increase sensitivity to chemically induced holoprosencephaly.

Photo Credit: Chris Frazee, Media Solutions
Rob Lipinski with Paul Hannam. Paul will be a senior at High Point University in North Carolina majoring in Biology. Rob served as Paul's mentor during the summer of 2007 for the UW-Madison Summer Research Opportunities Program.

Memberships
Society of Toxicology, Society for Developmental Biology

Interests/Hobbies
Frisbee, Extreme Bocce ball, Traveling

Current Funding
National Institute of Environmental Health Sciences
T32 ES 007015 (January 2004-December 2006)
Molecular and Environmental Toxicology Pre-& Postdoctoral

Publications
Lipinski RJ, Hutson PR, Hannam PW, Nydza RJ, Washington IM, Moore RW, Girdaukas GG, Peterson RE, Bushman W. "Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the Hedgehog signaling antagonist cyclopamine in the mouse." Toxicol Sci. 2008 Apr 14 [Epub ahead of print].

Lipinski, R.J., P.R. Hutson, P.W. Hannam, R.J. Nydza, I.M. Washington, R.W Moore, Gary G. Girdaukas, Richard E. Peterson, and W. Bushman (2008). Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the Hedgehog signaling antagonist cyclopamine in the mouse. In Press. Tox. Sci.

Lipinski RJ, Dengler E, Kiehn M, Peterson RE, Bushman W.
(2007) Identification and Characterization of Several Dietary Alkaloids as Weak Inhibitors of Hedgehog Signaling. Toxicol Sci. 2007 Aug 28; [Epub ahead of print] PMID: 17728282 [PubMed - as supplied by publisher]

Zhang, J., R. Lipinski, A. Shaw, J. Gipp, and W. Bushman (2006). “Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines.” J. Urology. In Press.

Doles, J., C. Cook, X. Shi, J. Valosky, R. Lipinski, and W. Bushman (2006). "Functional compensation in Hedgehog signaling during mouse prostate development." Dev Biol 295(1): 13-25.

Lipinski, R. J., J. J. Gipp, J. Zhang, J. D. Doles and W. Bushman (2006). "Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling." Exp Cell Res 312(11): 1925-38.

Doles, J. D., C. M. Vezina, R. Lipinski, R. E. Peterson and W. Bushman (2005). "Growth, morphogenesis, and differentiation during mouse prostate development in situ, in renal grafts, and in vitro." Prostate 65(4): 390-9.

Lipinski, R. J., C. H. Cook, D. H. Barnett, J. J. Gipp, R. E. Peterson and W. Bushman (2005). "Sonic hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 during fetal prostate development." Dev Dyn 233(3): 829-36.

Fan, L., C. V. Pepicelli, C. C. Dibble, W. Catbagan, J. L. Zarycki, R. Laciak, J. Gipp, A. Shaw, M. L. Lamm, A. Munoz, R. Lipinski, , J. B. Thrasher and W. Bushman (2004). "Hedgehog signaling promotes prostate xenograft tumor growth." Endocrinology 145(8): 3961-70.

Posters
Human Dietary Alkaloids Inhibit Hedgehog Signaling. R.J. Lipinski, E.K. Dengler, W. Heideman, R.E. Peterson, and W. Bushman. Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, WI (Presented at SOT-2006 in San Diego).

Individual and cooperative activities of the Gli transcription factors in Hedgehog signaling. R. Lipinski and W. Bushman. (Presented at SOT-2005 in New Orleans and Society of developmental Biology-2005 San Fransisco).

Hedgehog signaling regulates the expression of Insulin-like growth factor binding protein 6 in the developing prostate. R. Lipinski and W. Bushman. (Presented at Society for Developmental Biology-2004 in Calgary, Canada).

Lipinski CV 2007.pdf

Lipinski_05082008.pdf Defense Seminar
for Rob Lipinski
Thursday
05/08/08
4:00-4:50 p.m.
Rm 1309 HSLC
750 Highland Ave
Title: Lessons from the one-eyed sheep; Environmental disruption of Hedgehog signaling and human birth defects.

Mouse embryos exposed in vivo to cyclopamine at E8.5 exhibit varying forms of lateral cleft lip

Date Last Updated: 05/01/2008 webteam@med.wisc.edu