Centerline Winter/Spring 2007

Research Feature: Environmental reproductive toxicology research

Unlocking the secrets of TCDD

Dioxin is one of earth's most poisonous substances. Deliberate dioxin poisoning-such as the kind that visibly ravaged 2004 Ukrainian presidential candidate Viktor Yushchenko-is rare. However, dioxin continues to generate concern as a widespread environmental contaminant, both for its toxic potency and its persistence in the food chain.

A halogenated dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is highly chemically reactive. The substance gained infamy in the 1970s when it turned up as a contaminant in the herbicide Agent Orange. Scientists soon proved that dioxin could produce birth defects in rodents. People can still be exposed to dioxin in a number of ordinary ways. In fact, uncontrolled burning-no longer industry-is now the primary threat. This includes forest fires, volcanic eruptions and, especially, backyard burning. (See DioxinFacts.org and EPA: Backyard Burning.) Therefore, scientists are trying to learn more about dioxin's effects on the body with the aim of contributing to future preventions and therapies for dioxin exposure.

Reinhold Hutz, a long-time WNPRC affiliate and professor of biological sciences at the University of Wisconsin-Milwaukee, is such a scientist. He has long known that dioxin can enter human and animal female reproductive systems and cause decreased fertility and pregnancy loss. But exactly how this happens is a mystery. A receptor known as the aromatic hydrocarbon receptor (AHR) is a major part of the puzzle, Hutz explains. "But getting from the AHR step to the fertility step is a black box," he says.

Dioxin Cells

Dioxin Cells: Pictured are consecutive histologic sections of a rhesus monkey ovary; incubated respectively (top to bottom panels) with control medium, radiolabeled TCDD, and radiolabeled TCDD plus excess unlabeled AHR-antagonist (blocks the AHR). The images reveal that there is specific binding of TCDD to AHR in antral ovarian follicles in rhesus, particularly to granulosa cells.

Fortunately, Hutz and his colleagues are lifting the lid on this black box. Just this year, Hutz and his associate Monika Baldridge demonstrated for the first time how radiolabeled 3H-TCDD specifically binds to the granulosa cells of antral follicles and other regions of the rhesus monkey ovary. Baldridge is an assistant professor of biology with the Division of Natural and Health Sciences at Carroll College in Waukesha.

The research duo's data appearing soon in the American Journal of Primatology indicate a 60-fold increase in binding with 3H-TCDD over that of control tissue specimens obtained from rhesus monkeys at the California National Primate Research Center and the Wisconsin National Primate Research Center. This binding was reduced to lesser levels seen in controls by adding the competitive antagonist alpha-naphthoflavone, a known receptor-blocking agent.

What's important about these findings is that they support the hypothesis that TCDD exerts its toxic effects in women, in part, by binding to the AHR. Hutz developed this hypothesis during his work in the mid-1990s with Richard Peterson, a professor at the UW-Madison School of Pharmacy and an expert on dioxin's effects in male rats. Helping advance this early research was Charles Chaffin, then Hutz's PhD student, now an associate professor of OB/GYN and Reproductive Sciences at the University of Maryland, Baltimore. Master's student Heather Ho was also on the project, as was Gen Watanabe from Tokyo University of Agriculture and Technology (and former post-doctoral researcher with Primate Center senior scientist Ei Tersasawa).

Hutz has long conducted dioxin research in humans as well. In the mid-1990s, he non-invasively obtained granulosa cells from hormonally stimulated women participating in in-vitro fertilization programs in Chicago and Milwaukee. He cultured these cells with various concentrations of TCDD, then studied the toxin's effect on estrogens and other sex steroids and on inhibins A and B, hormones that control FSH secretion, follicle development, and embryonic and fetal development. He found that estrogen secretion was drastically reduced, and that inhibin B production was not altered by the toxin, but that inhibin A production increased significantly after four hours of exposure to both nanomolar and micromolar TCDD concentrations. By eight hours of exposure, human luteinizing granulosa cells exhibited a pronounced increase in inhibin A, nearly quadrupling secretion from unexposed control cells. TCDD exposure continued to increase inhibin A secretion at picomolar concentrations by 24 to 36 hours.

"If inhibin A goes up, follicle-stimulating hormone typically goes down," Hutz explains. "So, along with our AHR-signaling hypothesis, dioxin could impact fertility by inhibiting ovarian follicular growth."

Hutz's interest and expertise in reproductive toxicology have led him to conduct similar experiments in rats, hamsters and guinea pigs. More recently, his studies on TCDD have expanded to include zebrafish: In 2005, he found that this endocrine disruptor at low-levels, but at chronic dietary concentrations, decreased egg production by more than 50% and spawning success by as much as 96%. This research has advanced with Mike Carvan at the Great Lakes Water Institute.

Hutz's research techniques with various species include molecular (RT-PCR, RPA, in-situ hybridization), ICC, western immunoblotting, immunofluoresence, cell culture, histology, autoradiography, electron and light microscopy; also, laparotomy, laparoscopy, ultrasonography, histology/histochemistry, fluorescence microscopy, autoradiography, radioimmunoassay, radioreceptor assay, radio-chemistry, and enzyme assays.

Atresia research

In addition to learning how dioxin modulates estrogen receptor signaling and disrupts fertility, Hutz has studied how steroids and xenobiotic toxicants other than dioxin-such as PCBs-regulate ovarian function. He has particularly focused on the role natural estrogens, endocrine disruptors, and various growth factors play in atresia (apoptosis/degeneration) of ovarian follicles. "Atresia is why multiple births are naturally rare," he explains. "Estrogen produced by one follicle seems to inhibit the development of the other follicles. It's an exquisite interplay between estrogen from the follicle and FSH from the anterior pituitary gland. And it's very tightly regulated because, in women with fertility problems, doctors will give women FSH-and suddenly their ovaries are overstimulated and multiple eggs are ovulated."

More about Dr. Hutz-

Reinhold Hutz
Reinhold Hutz was born in Salzburg, Austria, and raised in Chicago. He holds a B.S. (1978) and an M.S. (1980) from Loyola University of Chicago. He earned his Ph.D., at Michigan State University in 1983. He completed his postdoctoral research associate training at the Primate Center from 1983 to 1986. He is an active member of the UW-Milwaukee Speakers Bureau and is an investigator and former deputy director of the National Institute of Environmental Health Sciences-Marine and Freshwater Biomedical Sciences Center at UWM. He also conducts research and provides expertise to the Great Lakes Water Institute, part of the Wisconsin Aquatic Technology and Environmental Research Center. He teaches four courses at UWM: physiology of reproduction, anatomy and physiology II, animal physiology, and an honors seminar in assisted reproduction. He is a Fulbright Senior Specialist through 2008, and spent several weeks collaborating at Tokyo University of Agriculture and Technology over the past few years. He has earned numerous professional honors, including "Who's Who in America" and "Who's Who in the World" recognitions, and has published more than 95 scientific manuscripts in peer-reviewed journals.

In the 1980s, Hutz showed that subcutaneous administration of estrogen via capsules induced atresia of the preovulatory or dominant follicle in rhesus monkeys in vivo. This work was conducted with former WNPRC senior scientist Don Dierschke and past Physiology Department Chair Richard Wolf. Both men became professors emeriti. (Wolf is now deceased.)

The researchers discovered that some of the inhibitory effect was mediated at the level of the hypothalamus and pituitary, and some directly at the ovarian level. Their monkey model strongly suggested that it was estrogen from the dominant follicle that was causing surrounding follicles to die, but that there were other factors as well.

"We now know that these factors can include steroids, growth factors such as nerve growth factor, cytokines, peptide hormones, xenobiotics such as dioxins, and angiogenic factors," Hutz details. "A complicated network drives the overall regulation of folliculogenesis and fertility."

Beyond the lab

Hutz points out that his work well represents why monkeys are good biomedical models for humans: "We have been able to do things you can"t do in humans. We can get whole ovaries and section and scan them with sophisticated image analysis." Hutz contrasts this to the 1970s and early '80s, when scientists gave oral doses of dioxin to female rhesus monkeys. "Now we can do the research noninvasively. We don't need to use the whole animal," he says. "It's easier to work with just ovarian tissues or cells and we can learn a great deal more. We definitely rely on the NPRCs' tissues and specimens programs for our work." The next step, he says, is to elucidate the mechanisms elicited after TCDD binds to the AHR in primates, both monkeys and women.

He adds: "I don't necessarily consider myself a primatologist per se, but a researcher using primate tissues to answer questions I can't answer any other way."

Those who know Hutz might partially argue his self-definition. Like many scientists working with nonhuman primates, Hutz works hard in the lab, and he also works hard to promote the conservation of ape, monkey and prosimian species. He has been crucially active in the International Primatological Society and other national and international societies. He has worked with many students and colleagues who have ventured forth to work in conventional academia, as reproductive physiologists at zoos, for pharmaceutical companies, and as heads of human in-vitro fertilization (IVF) laboratories and clinics.

Hutz's vast experience in both the biomedical research and primate conservation biology fields led to his peers asking him to be an on-line mentor on Primate Info Net's popular Careers in Primatology website. His closing statement on this site reads as follows:

"The future for employment prospects is always difficult to assess, but it is expected that non-human primate models will continue to be used as models for AIDS and other human disorders (including reproductive dysfunction), and that therefore this field will thrive."

References:

Baldridge MG, Hutz RJ. Autoradiographic localization of aromatic hydrocarbon receptor (AHR) in rhesus monkey ovary. Am J Primatol. 69:1-11, 2007.

Ho HM, Ohshima K, Watanabe G, Taya K, Strawn EY, Hutz RJ. TCDD increases inhibin A production by human luteinized granulose cells in vitro. J Reprod Dev. Aug;52(4):523-8, 2006. Epub Apr 21, 2006.

More references

Research Highlight

New model for testing AIDS vaccines

New AIDS research published in the Journal of Infectious Diseases features the work of the Wisconsin National Primate Center's Immunogenetics and Virology Unit, led by Eva Rakasz and Thomas Friedrich.

About 40 million people are currently infected with HIV worldwide. It is thought that the vast majority of these infections are spread through heterosexual contact, but the way in which the virus actually invades the body has remained mysterious. One of the most vexing questions was also one of the most basic: How much virus does it take to establish an infection? Primate Center researchers therefore developed a nonhuman primate model of heterosexual HIV transmission. They challenged female cynomolgus macaques with varying amounts of peripheral blood cells infected with a highly virulent strain of simian immunodeficiency virus (SIV).

Previously, infection in macaques could only be assured by delivering extremely high doses of cell-free virus, doses that were much larger than those encountered during sexual transmission of HIV. "We established persistent viremia with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus," said Rakasz. "This model will be indispensable for testing vaccines and topical agents aimed toward preventing heterosexual transmission of HIV." According to the researchers, topical microbicides are showing promise as agents for preventing HIV infection in women. Their model represents an important step forward in evaluating these important new drugs.

Also on the project were Masahiko Kaizu, Andrea Weiler, Kimberly Weisgrau, Kathy Veilhuber, Gemma May, Shari Piaskowski, Jessica Furlott, Nick Maness, John Loffredo and Amy Usborne.

Reference:

Kaizu M, Weiler AM, Weisgrau KL, Vielhuber KA, May G, Piaskowski SM, Furlott J, Maness NJ, Friedrich TC, Loffredo JT, Usborne A, Rakasz EG. Repeated intravaginal inoculation with cell-associated simian immunodeficiency virus results in persistent infection of nonhuman primates. J Infect Dis. 2006 Oct 1;194(7):912-6. Epub 2006 Aug 29. PMID: 16960778

New UW-Madison research program tackles Parkinson's disease

By Jordana Lenon,
UW-Madison press release
Dec. 14, 2006

A new research collaboration at the University of Wisconsin-Madison aims to move promising new therapies for Parkinson's disease from primates to patients.

Based at the Wisconsin National Primate Research Center and named the Preclinical Parkinson's Disease Research Program, the collaboration became official in November. Joseph Kemnitz, professor of physiology and Primate Center director, is the program's executive director. Renowned Parkinson's disease expert Marina Emborg, senior scientist at the Primate Center and in the Department of Anatomy, is scientific director.

"Our goal is to hasten discoveries that will lead to new therapies for Parkinson's disease, with an emphasis on cell and gene-based therapies," says Kemnitz.

Through the new program, the Primate Center is poised to become the country's centralized resource for Parkinson's disease research using nonhuman primate models, especially macaques, Kemnitz says. Program collaborators and funding agencies that will help develop the necessary laboratory and animal resources at the Primate Center include WinCon, a biotechnology company in Nanning, Guangxi, China; researchers at the Beijing Institute of Geriatrics, and an anonymous foundation.

"Macaques are regarded by many as the most useful model for Parkinson's research," Kemnitz says. "These collaborators chose the Wisconsin National Primate Research Center because we have a well established infrastructure for conducting research using nonhuman primates, and UW-Madison has a broad range of expertise directly relevant to this program."

That expertise lies in the UW-Madison's renowned capabilities in brain imaging technology, stem cell biology and clinical biomanufacturing. Researchers from the Primate Center, Waisman Center, School of Medicine and Public Health, School of Pharmacy, and other campus entities are already developing promising Parkinson's therapies based on embryonic stem cell derivations, trophic (nutritive) factors, compounds called thiazolidenediones, deep brain stimulation and other treatment avenues.

"We're committed to finding a cure for Parkinson's disease," Emborg says.

Information Services is new WNPRC Division

The Information Services Division, established this year and directed by Cynthia Robinson, joins Research Services, Animal Services, and Operational Services in supporting the research and outreach missions of the Wisconsin National Primate Research Center at the University of Wisconsin-Madison.

Information Services (IS) consists of three units: the Lawrence Jacobsen Library, led by Cynthia Robinson, the Information Technology and Systems Services Unit, led by Tom Lynch, and the newly established, yet-to-be populated Informatics Unit. These units will work closely together to provide a continuum of information services and resources on behalf of the Primate Center.

Although the three IS units will work together toward advancing information services, they have different day-to-day missions: The Jacobsen Library & Information Service acquires, organizes, develops, provides access to, and delivers information services and resources to Center scientists and staff, as well as the broader primatological and biomedical research communities. Information Technology and Systems Services provides network and computing services that meet the needs of Center scientists and staff. The unit is responsible for administering microcomputers (predominantly Apple based), providing print and network services, general-purpose data management and storage (UNIX servers), data and network security, as well as graphical and digital imaging services. Informatics will support a data sharing and collaboration environment both within the Wisconsin Center and across the eight NPRCs. It will be responsible for implementing the Informatics Strategy and supporting a unified NPRC approach to data sharing.

Jacobsen Library

The Lawrence Jacobsen Library has long been committed to sharing resources with the broader primatology and biomedical communities and has taken a lead role in applying new and innovative technologies in support of this objective. The library hosts two discussion lists-Primate-Science, with 709 members and the Primate Enrichment Forum with 251 members-and offers an on-line news clipping service, Primate-News, with 882 members. The library also now supports RSS file format feeds for Primate-Jobs and Primate-News. AskPrimate received 449 questions and Primate Info Net received over 7.25 million hits in 2005. That July, the library released its initial set of 21 in-depth Primate FactSheets, which received over 250,000 hits in October.

"Eventually we hope to have an in-depth fact sheet for every living primate species," says Robinson. "It's an ambitious goal, but one that will contribute immensely to the overall understanding of non-human primates."

By April 2006, Primate Info Net was averaging over 1.4 million hits per month. Document Delivery continues to be a popular service with the other NPRCs (5,762 requests handled in 2005). Furthermore, the PrimateLit database is now available free, via the web, to the U.S. and international research communities. During 2005, there were approximately 172,557 PrimateLit searches for its abstracts and full text articles. Careers in Primatology, Primates in Biomedical Research, and the International Directory of Primatology are other popular sites.

The library houses a collection of 7,100 books, 300 journal/newsletter titles, 1,000+ videotapes, 15,000 slides (currently being digitalized for release on the web), 200+ rare books, a children's book collection, the June Northrop Barker Archives, and the Callicam live streaming video of the Primate Center's marmosets.

In August 2000, the Jacobsen Library received a five-year P40 grant (RR015311) titled, "Coordinated Information Services for Primate Research." This grant allowed the library to continue to develop and expand its Internet services and resources. Cynthia Robinson succeeded retiring Larry Jacobsen as the library's director and PI on the grant in July 2003. Robinson successfully submitted the competitive renewal for the P40 grant and it was renewed in 2005 for an additional 5-year period.

In December 2005, the Primate Center Library was renamed "The Lawrence Jacobsen Library" to honor its long-time first director.

Information Technology and Systems Services

This unit is responsible for the Center's information technology infrastructure. During the previous five-year period, ITSS implemented a high-speed Internet firewall designed to protect the Center's servers, systems and data from attack by those attempting to exploit flaws in operating systems or services. Staff members also added an automated data backup system and continue to improve it. Network facilities were upgraded through the Graduate School as part of the campus-wide XXI Century Network Initiative. The upgrades also enabled the Primate Center to take advantage of high-speed networking initiatives like Internet2 and Abilene.

ITSS continues to support UNIX services, e-mail, the Primate Center website and Primate Info Net. Unit experts provide a digital imaging and graphics support service. One of the major roles of the Data Management Unit is the administration of the center's major research and production databases, i.e. animal records. Working with Animal Services, the unit has implemented a web-based veterinary medical records system built on top of the colony records database. This system provides a web interface to the animal records database for the entry of clinical data by veterinary staff. In addition, ITSS began a redesign of the Center's financial system and implemented a web-based solution that streamlined and simplified the process.

Informatics

The Informatics Unit, which will support a data sharing and collaboration environment both within the WNPRC and across the eight NPRCs, will be primarily responsible for implementing a new Informatics Strategy and supporting a unified NPRC approach to data sharing.

Two years ago, WNPRC administrators, along with consultant John Nylander of NyTech Strategic Planning, embarked on an informatics strategic planning process. Recognizing the importance of collaboration and data sharing, center employees invested much of their time and resources to develop an understanding of what needed to be done to advance these services. The resulting WNPRC Informatics Strategy is taking the idea of sharing information and data to a higher level via the creation of a "systems environment." This is a specially developed, specific hardware platform and operating system intended to support research activities germane to the primate research community.

"This system will be able to support the rapid sharing of on-line research tools, data sets, large biomedical image files, best practices, and more," Robinson explains. The Informatics Unit, in particular, she said, will have the primary responsibility for implementing the strategy and supporting a unified NPRC approach to data sharing.

"Mass Spec" has many uses

Two years ago, the Primate Center purchased a big, boxy set of machines called a mass spectrometer. One of many new instruments transforming the look of research labs and clinics today, "mass spec" is a powerful analytical technique that is leading the way in the study of proteins and metabolites.

"Mass spectrometer applications range from finding disease-causing mutations in proteins to identifying differences in how patients absorb and metabolize drugs," writes Laura Bonetta in NCRR Reporter, Summer 2006. "Mass spectrometers allow scientists to sift through thousands of different molecules in a complex biological soup according to their different chemical compositions, creating a 'spectrum' of their masses."

The WNPRC Assay Services Unit, which houses the new unit, is using mass spectrometry for several projects, according to Toni Ziegler, unit chief. "Our first completed project involved looking at multiple steroids for rhesus monkeys, with Dave Abbott as the investigator. We examined levels of estradiol, estrone, testosterone and other androgens in both maternal and fetal rhesus."

Adds Abbott, who submitted his first research paper using the mass spec in December, "The unit has permitted insight into the world of fetal endocrine disruption in rhesus monkeys and has revealed fetal and infant hormone abnormalities that are harbingers of adult pathology to come." Abbott, a professor of OB/GYN, is one of the country's foremost experts on the etiology of polycystic ovary syndrome. He has researched the topic for the past 20 years at the Primate Center.

Assay Services is currently using high performance liquid chromatography and mass spectrometry (LC/MS) for examining measurements of the social bonding hormones oxytocin and vasopressin. "We're using LC/MS as our gold standard-we're comparing our other methodologies to it," Ziegler describes. "We hope it will not only become another method that investigators can use, but that it will prove to be the best method for our clients."

Other methods Assay Services employs to hormone analysis include radioimmunoassay (RIA), immunoradiometric assay (IRMA), enzyme immunoassay (EIA), electrochemiluminescence (ECL), bioassay, celite chromatography, custom radio-iodination, protein determination. (See WNPRC Assay Services Unit for more information.)

There are some challenges to using the new equipment. Users must invest heavily in training to realize the unit's full potential of capabilities. "And we found that the system has to be kept very clean; it requires extensive maintenance," Ziegler says.

Mass spec goes slowly, she added. "But once it's done running, you have a fantastic method of measuring multiple hormones very accurately."

Mass Spectrometer Equipment

Mass Spec Equipment: The Primate Center's mass spectrometer has three basic parts-an ionization source, analyzer and detector. The first unit (left) turns molecules into gas, gives them a charge and converts them to ions. The second separates the ions according to their mass-to-charge ratios. The third unit (and sometimes additional steps) allow researchers to detect, or identify mass, abundance, elemental composition, and structure of ionized hormones and other substances.

Mass spectrometer screen

Mass Spec screen: This screen on the PC connected to the mass spec shows measurements for progesterone. As the sample moves through the machine, the different steps light up in green to indicate cycle stages in real time and to reveal exact measurements as the assay proceeds.

A decade of Primate Center embryonic stem cell firsts

A brief timeline of ES breakthroughs by WNPRC scientists:

  • 1995-James Thomson became the first to successfully isolate and culture rhesus monkey ES cells at the Wisconsin Regional Primate Research Center (PNAS).
  • 1996-Thomson repeated this feat with common marmoset ES cells (Biol Reprod).
  • 1998-Thomson published the neural differentiation of rhesus ES cells (APMIS).
  • 1998-Thomson's famous breakthrough growing human ES (hES) cells was published in Science. (This research occurred off campus, with private funding.)

Many subsequent hES cell "firsts" were accomplished by scientists who conducted lengthy training with James Thomson and/or Ted Golos, core reproduction and development scientists at the Wisconsin National Primate Research Center. These highlights include the following recent accomplishments:

  • 2003-Post-doctoral trainee Thomas Zwaka (now at Baylor College of Medicine) achieved homologous recombination with hES cells. A method for recombining segments of DNA within stem cells, the technique made it possible to manipulate any part of the human genome to study gene function and mimic human disease in the laboratory dish (Nature Biotechnology).
  • 2004-Post-doctoral trainee Behzad Gerami-Naini (now at Harvard University) developed a hES model that mimics the formation of the placenta, giving researchers a new window on early development (Endocrinology).
  • 2005-Longtime WNPRC-trained scientist Igor Slukvin, who worked with Golos and Thomson and now has his own lab at the Primate Center, and his post-doc Maxim Vodyanik became the first to culture lymphocytes and dendritic cells from human ES cells (Blood, J Immunol).
  • 2005-WiCell's Ren-He Xu, previously a post-doctoral trainee at the WNPRC (now at University of Connecticut), grew hES cells in the absence of mouse-derived feeder cells (Nature Methods).
  • 2006-Tenneille Ludwig, a 10-year scientist (grad student/post-doc/assistant scientist through the Primate Center with Barry Bavister, then James Thomson), formulated a media that will support hES cells without the need for contaminating animal products (Nature Biotechnology). Co-authoring the work was another former Primate Center post-doc, Mark Levenstein (now at WiCell).
Stem cell blastocysts

Stem Cell Blastocysts: Vivienne Marshall's classic photo of marmoset blastocysts from the 1990s. (See Spring 1997 Centerline for some marmoset ES cell history.)

NIH-National Center for Research Resources supported Primate Center scientists and collaborators conduct their work on campus with federally approved hES cell lines. The WNPRC is one of only two in the country-the other being the California National Primate Research Center-that is deriving new nonhuman primate embryonic stem cell lines for basic reproduction and development research, as well as for use in transplant medicine.

In addition to being Primate Center scientists, Drs. Thomson (Professor of Anatomy), Golos (Professor of OB/GYN) and Slukvin (Assistant Professor of Pathology and Laboratory Medicine), are part of the Stem Cell Training (SCT) Program at the UW-Madison. Their mission is to train the future generation of stem cell researchers. The SCT program is funded by a training grant from the NIH National Institute on Aging.

Gleanings

New grants

Wendy Saltzman, assistant professor of biology, University of California-Riverside, has received a two-year grant from the NIH-NIMH titled "The role of corticotropin-releasing factor in primate maternal behavior." The grant will fund her research with David Abbott at the WNPRC on the effects of stress on maternal behavior in marmosets. Saltzman and her group will investigate how stress affects maternal and abusive behavior, and will aim to determine what role the neuropeptide corticotropin-releasing factor plays in these effects.

David Watkins, professor of pathology, and his AIDS vaccine research team is working with Timothy Zamb at the International AIDS Vaccine Initiative on viral vector studies as part of the recent $287 million grant from the Bill & Melinda Gates Foundation. The Gates grant funds a global network of 16 research teams collaborating to accelerate AIDS vaccine development.

Thomas C. Friedrich, assistant scientist and head of Virology Services, is a principal investigator along with David Watkins on a new two-year grant from NIH-NIAID titled, "Correlates of elite control of SIV."

"With this grant, we plan to study why a few animals successfully control infection with SIV in the absence of any vaccine or treatment. We hope that these monkeys can teach us what a successful immune response against the virus looks like, so we'll know how to tailor future vaccines." -Tom Friedrich

Marina Emborg, senior scientist, WNPRC and Department of Anatomy, netted a two-year grant Jan. 1, 2007, from a private foundation to study the development of GDNF-secreting human neural stem cells for the treatment of Parkinson's disease. The project will compare the neuroprotective properties of GDNF-secreting human neural stem cells, vs. GDNF delivered by lentiviral vectors, vs. unmodified human neural stem cells, vs. culture media in Parkinsonian cynomologus monkeys.

Ted Golos, professor of OB/GYN, received a NCRR grant in April 2006 entitled "A primate ES cell model for embryo implantation." Christina Kendziorski, assistant professor in the Department of Biostatistics and Medical Informatics, is collaborating on the four-year grant.

Eva Rakasz, associate scientist and head of Immunology Services, has garnered a one-year grant from the American Foundation for AIDS Research titled, "Female genital ulcer as a portal of HIV entry." The research uses cynomolgus macaques.

Renewed grants

WNPRC senior scientist Dan Dumesic, also of Reproductive Medicine & Fertility Associates in Minnesota, has a one-year renewal with David Abbott, senior scientist and professor of OB/GYN, from NIH-NIMH to study paracrine dysregulation of oocyte competence in polycystic ovary disease. David Abbott also has a one-year renewal to research genes, androgens, and intrauterine environment in polycystic ovary disease. The grant is a subcontract to Northwestern University.

Ei Terasawa's National Institute of Child Health and Human Development grant, "Hypothalamic control of gonadotropin secretion," has been funded for its 22nd funding year and will continue at least another five years. The total direct cost alone and with indirect costs for five years will be $1.3 million and $1.9 million, respectively. Her team investigates membrane action of estrogen and the mechanisms of oscillatory neurosecretion in LHRH neurons. Terasawa is a WNPRC senior scientist and professor of pediatrics.

Rick Weindruch's long-term study of the links between diet and aging in monkeys will continue through 2011 with the help of another $7.9 million grant from NIH-NIA. The study was initiated in 1989 to examine the effects of a reduced-calorie diet without malnutrition on the aging process, health and lifespan of 76 rhesus monkeys. Weindruch is a professor of medicine, geriatrics and gerontology.

Meetings

The Primate Center hosted the Steering Committee Kickoff Meeting for the National Primate Research Centers Pathology Image Database on Dec. 14.

The Twenty-Ninth Meeting of the American Society of Primatologists occurred in San Antonio, Texas, August 16-19, 2006.

The Marmoset Research Group of the Americas hosted its second annual meeting August 15-16, 2006, at the Southwest National Primate Research Center in San Antonio, Texas.

The 24th Annual Symposium on nonhuman primate models for AIDS occurred Oct. 4-7 in Atlanta. The Yerkes NPRC hosted the meeting.

Recognitions

WNPRC Affiliate Ian Duncan, professor of neurology, was elected last March to the Corresponding Fellowship of the Royal Society of Edinburgh, Scotland's National Academy.

Facilities news

Construction on the Interdisciplinary Research Complex, or Healthstar building, is underway on a site outside the Clinical Research Center, across from the Waisman Center, on the site of parking lot 63. The Primate Center will occupy space in this building for research and animals.

Colony changes

The Primate Center colony houses about 1,186 rhesus macaques, 53 cynomolgus macaques and 266 common marmosets. The Center's 19 vervets, acquired in 2004, were transferred to another research facility last fall.

In the news

"UW Team In Hot Pursuit of Elusive HIV Vaccine" was the front-page story in the Wisconsin State Journal June 27. The article featured the latest developments in AIDS research at the UW-Madison's HIV lab under the direction of David Watkins. Madison WISC TV also ran a segment, "War on AIDS," June 29 on Live at Five. The segment addressed both the research and the annual summer bike ride that benefits the Madison AIDS Network. Finally, the heterosexual virus transmission findings of Eva Rakasz and Tom Friedrich were covered by the Wisconsin State Journal on Dec. 3. (See research highlight this issue.)

A stem cell documentary crew visited campus and the Primate Center July 11-12. Jessica Gerstle, formerly a producer at Dateline NBC, worked with Daisy Manning of WiCell and formerly at the Primate Center, to coordinate visits with UW-Madison stem cell scientists James Thomson, Jon Odorico, Tim Kamp, Marina Emborg, Jeff Jones and others. Jessica and her father Claude are producing this documentary together. A physician and MIT trustee who plans to narrate the film, Claude incurred a spinal cord injury in a bicycle accident several years ago.

"Hunter and Hunted-Kidnapped" aired on the National Geographic Channel in July and August. The program addressed the increase in conflicts between baboons and humans in South Africa. The show investigated one particular abduction of a child from his bed by a male baboon in 2003. Steven Shelton, distinguished researcher in the Department of Psychiatry, Wisconsin Psychiatric Institute & Clinics, was featured and served as scientific advisor on this show.

Our Center's largest grant, the Calorie Restriction and Aging program project grant has seen no slow down in media coverage. Now that the monkeys are entering their "early senior years," there has been a steady stream of reporters eager to write about, photograph and video-image the monkeys and interview principal investigator Rick Weindruch (WNPRC, VA-GRECC, Geriatrics Depts.) and WNPRC associate scientist Ricki Colman. Media coverage this year has included the Milwaukee Journal-Sentinel, Wisconsin Public Radio, The New York Times, Discover Magazine, NTV in Japan, Channel 4 in Great Britain, Télévision Francais I, Der Spiegel, Newsweek Polska, TV Record Brazil, La Tercera in Chile, MIT Tech Review, CNN's Paula Zahn Now, and ABC's Good Morning America and Nightline.

New WNPRC research page

The Primate Center's main menu research link has been overhauled to include more scientists' lab links as well as additional resources for researchers and the public. Scientific journal articles from WNPRC staff and affiliates are also linked to this page.

Invited talks

Ricki Colman, WNPRC associate scientist, and Rick Weindruch, professor of medicine, Geriatrics & Gerontology Section, were invited speakers at the American Aging Association's 35th Annual Meeting, "Interventions in Aging and Age-related Diseases: The Present and the Future" June 2006 in Boston. Colman also spoke at the Gerontological Society of America's annual meeting in November. She spoke on long-term dietary restriction effects on osteoarthritis in rhesus monkeys.

Marina Emborg, WNPRC senior scientist and Department of Anatomy, presented, "Gene therapy in non human primate models of Parkinson's disease" at Amgen, Thousand Oaks, California, in December. She was an invited speaker at the Congress of Neurological Surgeons' October Annual Meeting in Chicago, where she and her colleagues delivered, "Lentiviral Delivery of GDNF in aged MPTP-treated rhesus monkeys." Emborg spoke last year at the annual meeting of the Gerontological Society of America in November and chaired its Parkinson's Disease Symposium and satellite workshop titled, "Non human primate resources for Parkinson's disease." She presented "Preclinical models of Parkinson's disease" at the Stem Cell Network Workshop: Model Systems and Parkinson's disease, at Dalhousie University, Halifax, Canada, last February. She also chaired the workshop's Animal Models Session. Finally, she is the program director for the 2007 American Society for Neural Therapy XIV Annual Meeting in May.

Ted Golos, professor of OB/GYN, was an invited speaker at the Serono International Symposium on Stem Cells in Reproductive Medicine March and April in Valencia, Spain. He was also an invited speaker at the Meeting of the International Federation of Placenta Associations in Glasgow, Scotland, and at the Greenwald Symposium on Reproduction in Kansas City, Kansas, both in August. He is scheduled to be an invited speaker at the Annual Meeting of the Society for Gynecologic Investigation in Reno March 2007.

Erwin Montgomery, professor of neurology and director, Movement Disorders Program, Department of Neurology, was a guest speaker at the Wisconsin Psychiatric Association's 2006 Annual Conference, "Update in Biological Issues" March and April in Kohler, Wisconsin.

David O'Connor, assistant professor of pathology and laboratory medicine, spoke on "MHC-matched Mauritian cynomolgus macaques" at the NCRR Rhesus Macaque Genetics Workshop in Bethesda, Maryland last April. He also presented his results at the 2005 Seattle International Conference on Primate Genomics in April. He delivered "Extremely common MHC Class I alleles in Mauritian cynomolgus macaques" at the 3rd IAS Conference on HIV Pathogenesis and Treatment in Brazil in July. He addressed "Advances in nonhuman primate MHC genetics" as the keynote speaker for the September 2005 Nonhuman Primate Assays workshop in Atlanta, Georgia. O'Connor also participated in educational outreach programs in South Africa, and regularly engages in local outreach efforts, including working with clinicians from UW-Hospitals to study the pathogenetics of HIV infection.

Steven Shelton, distinguished researcher in the Department of Psychiatry, and Ned Kalin, professor and chair of the Department of Psychiatry, will host the International Society of Psychoneuroendocrinology meeting in August 2007, in Madison, Wisconsin. In July, they also hosted the National Institute of Mental Health workshop on Emotion Regulation, which is part of the Mental Health Conferences on Comparative and Primate Research series. Steve Shelton gave the Presidential Welcoming Address to the 4th Regional Congress for Eastern & Central Europe in Vilnius, Lithuania, last June. Ned Kalin also presented his research in May at the Society of Biological Psychiatry in Toronto.

Igor Slukvin, assistant professor of pathology and laboratory medicine, spoke on "Generation of Myeloid Dendritic Cells from Human Embryonic Stem Cells" at the 93th Annual meeting of the American Association of Immunologists in Boston last May. He presented, "Dissecting of Hematopoietic and Endothelial Developmental Pathways Using Human Embryonic Stem Cells" at the University of Connecticut Health Center in Farmington in October. He is scheduled to offer "Human ES cells as a Model for Hematopoietic Development and a Source of Hematopoietic Cells for Cellular Therapy" at University of California, Riverside in May 2007.

James Thomson, a John D. MacArthur professor of anatomy with scientific appointments at the WNPRC, Genome Center, WiCell, National Stem Cell Bank, Stem Cell Products, Inc., and Cellular Dynamics, Inc., presented "Human embryonic stem cells" in September as the President's Keynote Address at the Annual Meeting of the Safety Pharmacology Society in San Diego, and in October at the Nathan R. Brewer Special Topics Lecture, 57th American Association for Laboratory Animal Science (AALAS) National Meeting in Salt Lake City. He spoke on the "Business potential of human embryonic stem cells" in October at the CEO Summit, Fluno Center for Executive Education, in Madison.

David Watkins, professor of pathology and director of the UW-Madison/WNPRC AIDS Vaccine Research Lab, is an invited speaker at "HIV Vaccines: From Basic Research to Clinical Trials" at the annual Keystone Symposia in Whisler, British Columbia, Canada, this coming March.

Rick Weindruch, professor of medicine, geriatrics and gerontology, presented several talks in 2006. They included: "Calories, Cancer and Aging" at the University of Pittsburgh Cancer Center, Pittsburgh; "Caloric restriction and aging: Studies in mice and monkeys," Bollum Symposium on the Science of Aging, University of Minnesota, Minneapolis; "Insights from gene expression profiling of the influences of caloric restriction on nuclear receptors," NIA Workshop on Nuclear Receptors and Aging, Potomac, Maryland; "Caloric restriction and aging: Studies in mice and monkeys," Sirtris Pharmaceuticals, Cambridge, Massachusetts, and "Caloric intake and aging," Technology Review's Emerging Technologies Conference at MIT in Cambridge. In 2007, Weindruch will speak at the Experimental Biology meeting in Washington, D.C., and also at the 36th Annual Meeting of the American Aging Association in San Antonio. Weindruch is also an investigator with the Geriatric Research, Education and Clinical Center (GRECC) at the Veteran's Administration Hospital.

Toni Ziegler, WNPRC senior scientist and director of Assay Services, spoke last February on, "Neuroendocrine responsiveness of male cooperatively breeding monkeys to female scent signals." The talk was an invited lecture to the Center for Reproductive Biology, Washington State University, Pullman, Washington. In November, she present on "The biological basis of paternal care in marmoset and tamarins: Why dads matter," as an invited lecture for the Biopsychology Unit at the University of Chicago.

Primate Center Planning

Two staff strategic planning sessions occurred Sept. 25 and Oct. 30. A revamped Internal Advisory Committee and staff website took shape this fall. The Center hosted research retreats to address progress and funding Sept. 14 and Dec. 11. Divisions and units are gearing up for the NCRR Site Visit on Jan. 25, following the submission of the Center's competing base grant renewal application in September 2006.