GRANT AWARDS

DOD grant for Camarero Julio Camarero has been awarded a $400,000, three-year grant from the Department of Defense PCRP (Prostate Cancer Research Program) of the Office of the Congressionally Directed Medical Research Programs for his project

“Screening and Selection of New Antagonists of the RING-Mediated Hdm2/Hdmx Interaction.” (more in p.5)

NIA clinical trial grant for Brinton and Zhao

Roberta Brinton and Liqin Zhao are co-principal

investigators on a three-year grant with a direct cost of $1.25 million from the NIA entitled, "Estrogen Receptor- PhytoSERMs for Management of Menopause and Age-Associated Memory Decline: Pilot Development Trials." Principal investigator is Lon Schneider, professor of psychiatry, neurology and gerontology from the Keck School of Medicine. (more in p.5)

Concept Award from DOD for Neamati Nouri Neamati, Helen Ha, Ph.D. candidtate, and Srinivas Odde, postdoctoral research associate, have been funded by

the Department of Defense Lung Research Program (LCRP) of the Office of Congressionally Directed Medical Research Programs (CDMRP). This is a two-page Concept Award for the amount of $75,000 direct cost for one year. The funded grant is entitled, “Development of novel CXCR2 inhibitors for the treatment of COPD and lung cancer.” (Please see the article, “One Drug, Two Diseases,” of this grant in the USC News). ■

WALTER WOLF, AFTER THE 50-YEARS-AT-USC CELEBRATION

My activities and goals for the future

I would like to thank profusely all those who came on November 7, 2009, to celebrate with my family, my friends and colleagues my first 50 years at USC, those who organized this festive occasion and those who, although unable to attend in person, were nevertheless present. It was a wonderful evening that I will cherish, and I am told by those who attended how much they enjoyed it. (more in p.6)

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A trimester publication for the faculty, staff, students, alumni and friends of the Department

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■■

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Dear colleagues:

I hope you will enjoy reading the activities that occupied our faculty, staff and students over the past few months.

Sincere congratulations go out to Drs. Brinton, Camarero, Neamati and Zhao for their continued grant success in this challenging environment.

The gala dinner for Dr. Wolf brought together many of our alumni to celebrate his achievements over the past 50 years and I know you will enjoy his essay as well as the photo collage celebrating this event.

Special thanks go out to Liz Gongora for making this such a special event for so many--we all know that Liz has many talents in event planning that continually benefit our department.

The Moving Targets symposium, held in conjunction with the AAPS meetings in Los Angeles in November, was likewise a great success and kudos go to our talented student AAPS chapter led by Jennifer-Ann Bayan, and to our faculty sponsors, Drs. Wei-Chiang Shen and Andrew MacKay.

I wish you all a happy and productive spring and remember, please keep us posted as to your professional activities, we love to hear from you! ■

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

3

OOTTHHEERR FFAACCUULLTTYY NNEEWWSS

Jim Adams Presented “Chumash Healing” at Pitzer College,

Claremont, Monday, November 23, 7PM. Interviewed by ATVN.org about medical marijuana in

Los Angeles, November 17. Presented "Estanislao's Revolution against the California

Mission System" at Historical Society of Crescenta Valley, November 16. ■

Roberta Diaz-Brinton Featured in a website video as part of the Investing in

Recovery and Discovery report, put together by United for Medical Research, which demonstrates the importance of NIH stimulus funding to policymakers and the public.

Attended Stanford Center for Neuroscience in Women’s Health in Stanford, CA, January 15-17 and speaker of the Window Opportunity of Estrogen Therapy for Neuroprotection Workshop: Estrogen Regulation of Mitochondrial Function in Brain Implications for Brain Metabolism, Prevention of Neurodegenerative Disease and Healthy Cell Bias of Estrogen Action.

Speaker at the Rockefeller New York Pop Council Meeting on October 23, 2009. Title of presentation: Progesterone, Nestorone and Brain Function: Effects of progestines on neuronal stem cell.

Speaker at the Society For Neuroscience Annual Meeting on October 20, 2009. Title of presentation: Steroid Hormone Aging Nanosymposium: Progesterone and clinical progestins differentially regulate proliferation of rat neural progenitor cells both in vitro and in vivo.

Attended the 12th Graylyn Conference on Women's Cognitive Health in Winston-Salem NC, October 13-14, 2009 and chaired the session on “Recent Findings on Hormones, Cognition and Aging.”

Attended Alzheimer’s Disease Center (ADC) Director Meeting, Baltimore MD, October 7-11, 2009 and presented on October 7at the Scientific Symposium: Therapeutics to Prevent and Delay Alzheimer’s Disease: Critical role for ADRCs in Translation Research.

Attended the Board of Scientific Counselors Meeting of the National Institute of Mental Health (NIMH) in Bethesda MD, October 5-7, 2009. ■

Marco Bortolato By invitation only, presented a poster at the 48th ACNP

(American College of Neuropsychopharmacology) Annual Meeting in Hollywood, FL, on December 6-10, 2009. Title: A novel hypomorphic monoamine oxidase A transgenic mouse exhibits low aggression and reduced serotonin levels in prefrontal cortex and amygdale. ■

Ronald L. Alkana Presented “The structure of extracellular domain Loop 2

markedly affects ethanol but not diazepam sensitivity of GABA-ARs” at 39th Annual Meeting of the Society for Neuroscience, Chicago, IL, October 17-21, 2009. ■

Enrique Cadenas Co-Theme Editor with Sarah Hamm-Alvarez:

Mitochondrial Medicine and Therapeutics, part II. Advanced Drug Delivery Reviews, 61(14): 1233-1388, 2009. (For the website, click here).

Plenary Lecturer at the VIth Conference of the Society of Free Radical Biology & Medicine South American Group. Lecture title: MAPK and insulin signaling in neurodegeneration. Santiago, Chile, 27-30 Sept 2009.

Lecturer at the INDO-USA Bilateral Forum on Redox Signaling in Degenerative Diseases. New Delhi, India, 19-21 December 2009. ■

Sarah Hamm-Alvarez Co-director of the USC Biomedical Nanoscience

Initiative that recently announced the completion of new Nanoscience Laboratories. (For more on this story click here. )

Co-Theme Editor with Enrique Cadenas: Mitochondrial Medicine and Therapeutics, part II. Advanced Drug Delivery Reviews, 61(14): 1233-1388, 2009. (For the website, click here).

Co-organizer of the Bionano Retreat at Descanso Gardens in La Canada Flintridge CA, on November 20, 2009

Attended the American Society for Cell Biology meeting in San Diego from December 5 to December 9, 2009. ■

J. Andrew MacKay Featured on Innovations Report website for his work

with a team of Duke scientists on the development of nano-scale drug delivery for chemotherapy. (For more of this story, click here; for more of MacKay’s nano-scale drug delivery research, click here.) ■

Bangyan Stiles Featured with PhD student, Jennifer-Ann Bayan, in an

article entitled, “One-Two Punch for Diabetes,” as compiled in a report by United for Medical Research on “Investing in Recovery and Discovery: How NIH Recovery and Reinvestment Act Grants are Improving Health and the Economy.” (For the report, click here; for more of Stiles-Bayan research, click here) ■

(more next page)

A trimester publication for the faculty, staff, students, alumni and friends of the Department

4

Julio A. Camarero Quoted in Chemical & Engineering News, on Britt E.

Erickson’s report, Spurring Innovation, about Dr. Camarero’s plans to use his T-R01 grant to develop a “new generation of specific protein-capture reagents for diagnostic or therapeutic purposes.” Camarero’s group plans to use cell-based libraries of cyclotides (microproteins that have unique properties) to select specific cyclotide sequences against particular protein targets, “somehow mimicking what our immune system does with antibodies,” he says.

Speaker, First Look LA, November 4, 2009, California Institute of Technology, Pasadena, CA. Title of presentation: Cyclopeptics: Providing a new class of therapeutics for the treatment of human disease,

Speaker, Barcelona BioMed Conference Peptide Engineering: Therapeutic Peptides, October 26-28, 2009, Barcelona, Spain. Title of presentation: Biomimetic approach for the bacterial synthesis of cyclotides.

Speaker, 1st International conference on circular proteins at the 8th Australian Peptide Conference, October 18-21, 2009, Heron Island, Australia. Title of presentation: Biosynthesis of folded cyclotides inside living bacterial cells.

Speaker, 3rd Annual PEGS (Protein Engineering Summit) Europe Conference, 1st Next generation technologies for protein science, October 6-8, 2009, Hannover, Germany. Title of presentation: Biosynthesis of folded cyclotides inside living bacterial cells. ■

Wei-Chiang Shen Speaker in the Symposium at Boston University to

celebrate the retirement of Prof. Richard A. Laursen, his Ph.D. advisor, in the Chemistry Department, on October 31, 2009. Title of talk: Cell-Penetrating Peptides: from Peptide Chemistry to Drug Delivery.

Visited Pfizer in St. Louis on November 18, 2009 and gave a presentation, entitled: Recombinant Fusion Proteins of Human Growth Hormone and Transferrin for Oral Delivery. Host was Dr. Wei Wang, an alumnus of PSCI.

Invited speaker in PepTalk Conference at Hotel Del Coronado, San Diego, January 14, 2010. Title of talk: Effect of Spacer Insertion on the Biological Activity, Production, and Pharmacokinetics of Recombinant Bifunctional Fusion Proteins. ■

Walter Wolf Honored by The Correlative Imaging Council Board of

Directors with a special Walter Wolf Award webpage on the CIC website. ■

Dr. Camarero is shown leaving Heron Island. “What better than a circular island to hold a conference on circular proteins,“ said Prof. David Craik from the University of Queensland, conference organizer.

A view from Dr. Camarero’s

room.

“The island was quite small (no cars or roads) just the resort and scientific station belonging to the University of Queensland. You could walk from one

side to the other in less than 10 minutes. It was a very interesting experience. The only way to get in and out of the island was by boat (2-hour trip) or

helicopter (45-minute flight). The reefs were beautiful with sharks included, but fortunately they were not aggressive,” Dr. Camarero observed.

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

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Basic science to therapeutic translation is becoming a reality by Liqin Zhao NIA CLINICAL TRIAL GRANT FOR BRINTON AND ZHAO (cont’d from p. 1)

This first-in-human clinical trial is a developmental plan that aims to translate a standardized formulation of phytoestrogenic molecules (PhytoSERMs), which selectively targets estrogen receptor (ER), into a therapeutic treatment of symptoms present in menopause. The Phase I study is designed to determine the safe/tolerate dosages and pharmacokinetic profile of the PhytoSERM formulation. The Phase IIA study is a 12-week proof-of-concept assessment for continuing safety/tolerability and potential efficacy for menopausal hot flashes and cognition in recent menopausal women. The PhytoSERM formulation was originally discovered and developed through the grant support (2005-2007) from Alzheimer’s Association awarded to Dr. Liqin Zhao (served as the PI) and Dr. Brinton (Co-Investigator). The formulation was first revealed to the scientific community at the 10th International Conference on Alzheimer’s Disease and Related Disorders in Madrid, Spain, in July 2006. The later preclinical development of the PhytoSERM formulation was supported by the generous Bensussen Fund provided to Dr. Brinton. USC owns a series of patents on this invention, on which Drs. Brinton and Zhao serve as Co-Inventors. USC Stevens Institute for Innovation is currently working on licensing and commercialization of this technology. For many years, one of the largest unmet medical needs in the health of menopausal women is an estrogen therapy that is both safe and effective. It is anticipated that this translational clinical research will lead to a novel alternative approach that would fill this gap. Moreover, owing to the unique nature of the high specificity for ER, which nullifies the feminizing activity as seen in non-selective estrogen-based therapy, Brinton and Zhao are looking beyond what they have discovered. They are currently working on obtaining the funding that will support their exploratory studies of the PhytoSERM formulation on male systems, targeting male hormones-related disorders, including hair loss and prostate health, as well as cognitive function. They also strive to expand their therapeutic development efforts into areas that will eventually lead to novel chemical entities and new applications. Related Publications: Zhao, L. and Brinton, R.D. WHI and WHIMS Follow-

Up and Human Studies of Soy Isoflavones on Cognition. Expert Review of Neurotherapeutics 7(11):1549-1564, 2007. PMID: 17997703

Zhao, L., Mao, Z. and Brinton, R.D. A Select

Combination of Clinically Relevant Phytoestrogens Enhances Estrogen Receptor -Binding Selectivity and Neuroprotective Activities In Vitro and In Vivo. Endocrinology 150(2):770-783, 2009. PMID: 18818291

(For more of Brinton’s lab research, click here). ■

CAMARERO (cont’d from p. 1)

"We anticipate that this novel type of cyclotide-based

inhibitor will have a broad spectrum of antitumor activity in human cancers, thus providing a novel basis for the future therapy of human cancers, including prostate cancer. Equally importantly, successful implementation of the proposed studies will provide a precedent for screening for cyclotides able to inhibit other RING-domain oncoproteins, or other types of oncogenic protein-protein complexes in prostate cancer: for example those that may induce tumor cell apoptosis independent of p53 or compounds able to reactivate mutant p53. These compounds could be used in combination with Hdm2 antagonists to prevent tumor relapse or secondary tumor formation," Dr. Camarero said. ■

The PhytoSERM Clinical Trial Working Group. From left to right: Kathleen Hurtado, Wendy Mack, Lon Schneider, Roberta Brinton, Liqin Zhao and Karen Dagerman

Zhao and Brinton at the 10th International Conference on Alzheimer’s Disease and Related Disorders, where The PhytoSERM formulation was first revealed, in Madrid, Spain, July 2006.

A trimester publication for the faculty, staff, students, alumni and friends of the Department

6

WALTER WOLF, AFTER THE 50-YEARS-AT-USC CELEBRATION My activities and goals for the future (cont’d from p.1)

My major regret, naturally, is that my dear wife could not participate in something she had been so instrumental in making possible and who had been my dear companion so much of my life.

Let me share with all of you, especially those who were unable to attend, some of the comments I made at the end of the evening, in which I discussed my plans for the future and how they were tied and a continuation of what I have been doing since joining USC in August 1959, and before.

As a scientist, I will continue striving to develop noninvasive imaging methods as key tools in the study of how drugs distribute in living systems and how they home in on their targets. The rationale for this approach is that if we want to capture the dynamic properties (kinetics) of living systems, we cannot do so if we perturb the system during measurements. It is therefore essential to continue the development of ever more accurate and sensitive methods that allow us to measure the dynamics of biodistribution and metabolism of drugs, and thereby provide a novel window on our understanding of their pharmacology and therapeutics. Such methods will be central in allowing scientists and clinicians to enable the art of medicine to move to the science of medicine.

It is currently rewarding how different threads of my past research may now come together in a major project that I am embarking: that of estimating the ultimate active molecular anabolites of a model drug at the tumor level, by combining two complementary imaging methods (PET and MRS), and by being thereby able to analyze physiological modes with as many compartments as necessary, using only those data generated from each single individual.

As a member of the academic community, my main commitments are complementary: I teach, I help create new knowledge and I help to ensure that all members of the academic community, at USC and elsewhere, have the freedom and the opportunity in meeting their academic goals.

At USC I am especially proud of having contributed to major changes in pharmacy as a health profession, both in the profession as a whole from its sole emphasis on the provision of products, to that of the provision and guidance in the proper utilization of pharmaceutical drug products – clinical pharmacy. And of having been able to develop the principle that the complexity of pharmaceutical drugs required both generalists and specialists. The establishment of Radiopharmacy in 1968 was a quantum change, and the importance and need of several other pharmaceutical specialties is now well recognized.

But that is what we did. There is so much more we need

to do in the future. The ultimate and ideal goal in health care would be to ensure that every human being is able to live a healthy and productive life as long as biology allows it, and that such life is of high quality. Proper health care needs to move from solving problems (diseases) when they occur to one where diseases can be prevented before they occur, as well as minimizing their effects when they elude such preventive steps. And because health care, just like science, is an interdisciplinary activity, the Pharmacist of the future should be the drug specialist of the health care team; and to be effective, a co-equal member of teams composed of physicians, nurses, pharmacists and other health professionals. The education of pharmacists and pharmaceutical specialists must evolve continuously to meet such goals.

As members of the Academy, a comprehensive term encompassing all academic activities, at USC and elsewhere, we have both opportunities and obligations. Opportunities because we can continuously create, expand and transmit knowledge; obligations because we must ensure that all members of the Academy have unfettered opportunities to do so. We do, however, live in a world where a pyramidal system (business model?) predominates. Most people work for someone or have others who work for them. We academics work WITH those members of the Academy whose function it is to manage and administer the system, not FOR them. Understanding and acting on such a subtle difference is not easy and continued education and vigilance is necessary. That is why faculty participation in the governance of the Academy is essential.

Finally, I am also – as we all are – a citizen, and as such, we all have obligations that go well beyond our commitments as scientists and as members of the academic community. Indeed, such obligations and activities are an integral part of who we are.

One of the principles of Judaism is that of Tikkun Olam – improving the world. We are part of humanity, and striving to improve the human condition at all levels defines us. I was fortunate that our family was able to escape in 1938 the darkest events of the 20th. century, and I was especially fortunate in having been able to be raised in Uruguay, one of the most enlightened societies and people I have known. But it is precisely because of this that strengthening Jewish life in the US, in Israel, and all over the world is central to allowing that we, as a people, continue spearheading the principles of Tikkun Olam.

Last, but not least, is my own family. The loss of my dear wife Gladys has deprived me not only of my lifetime companion, but has left a void that I am trying to cope with.

(more in p.11)

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

7

PPrrooffeessssoorr WWaalltteerr WWoollff tthhrroouugghh tthhee yyeeaarrss

TTooaasstt ttoo 5500 yyeeaarrss aatt tthhee SScchhooooll ooff PPhhaarrmmaaccyy

■

A trimester publication for the faculty, staff, students, alumni and friends of the Department

8

Distinguished Speakers:Top pictures (L) Dai Fukumura, Harvard Univ; (R) Walter Wolf. USC

Picture below (L-R): Hiroshi Maeda, Sojo Univ, Japan;Francis C. Szoka, UCSF; Jindrick Kopecek, Univ of Utah.

Not in the pictures are: Neil Gibson, Pfizer; Napoleon Ferrara, Genentech.

““MMoovviinngg TTaarrggeettss”” NNoovveemmbbeerr 99,, 22000099 88tthh AAnnnnuuaall MMuullttiiddiisscciipplliinnaarryy SScciieennttiiffiicc SSyymmppoossiiuumm RRaaddiissssoonn HHootteell,, LLooss AAnnggeelleess MMiiddttoowwnn @@UUSSCC ““DDrruugg DDeelliivveerryy aanndd TThheerraappeeuuttiiccss ttoo tthhee TTuummoorr MMiiccrrooeennvviirroonnmmeenntt””

Please click here for the website report of this event: “USC Symposium Targets Key Pharmaceuticals.”

AAPS-USC

Student Chapter Board and faculty

advisors (l-r): Bernice Aguilar, Randy Kenien, Vivian Galicia,

Jennifer-Ann Bayan,

Robert Mo, Andrew MacKay and Wei-Chiang

Shen.

School of Pharmacy Dean,

Pete Vanderveen and

Jennifer Ann Bayan, AAPS-USC Chair.

The School sponsored the

program with the American

Association of Pharmaceutical

Sciences (AAPS).

Poster competition honorable mention: Siti Mohd Janib from Andrew MacKay’s lab, shown with Francis Szoka, seminar speaker from UCSF.

Poster competition honorable mention: Melissa Millard from Nouri Neamati lab.

Other winners: o Stephen Timothy Buckley, Trinity College Dublin, Ireland, 1st place o Jingying Xu, USC Dept of Neuroscience, 2nd place o Kristen Jaruszewski, Florida A&M University, 3rd place o Dee Bojanic, UCLA, honorable mention

■

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

9

PPOOSSTTEERR PPRREESSEENNTTAATTIIOONNSS

AAPS (American Association of Pharmaceutical Sciences) Annual Meeting, Los Angeles CA, November 2009

J.A. Bayan, N. Zeng, B. Stiles: The paracrine effects of PTEN loss in pancreatic beta-cells.

L. Chiang, T. Tolmachova 2, J. Ngo1, A. N. Hume2, J. Schechter3, M.C. Seabra2, S. Hamm-Alvarez1,3:

Loss of Rab27a and b affects lacrimal gland acinar cell secretory pathway organization, morphology, and function.

R.T. Hamilton, J. Hwang, H.N. Hodis*, E. Cadenas: Protein unfoldedlow density lipoproteinregulates mitochondrial

bioenergetics and redox status via c-Jun-n-terminal kinase-2 phosphorylation: Implication for the atherogenic phenotype of coronary artery disease. *KSOM-ARU

S.N. Mohd Janib, J. Abid*, M. Pastuszka and J.A. MacKay: Nanoparticle self-assembly using genetically engineered polypeptides. *Univ of London, School of Pharmacy

J-C. Ren, I. Rebrin, W. Klichko*, W.C.Orr* and B. Sohal, R.S. Sohal: Decrease in expression of nuclear DNA encoded subunits of cytochrome c oxidase in fruit flies during aging. *Southern Methodist Univ

Ling Ren, L. Fei, J.L. Zaro, W. Shen: Mechanism investigation of the arginine-rich cell-penetrating-peptides

(CPPs). ■

ASCB (American Society of Cell Biology) Annual Meeting, San Diego CA, December 9, 2009

Shi Xu, Francie Yarber, Curtis T. Okamoto, Austin K Mircheff, and Sarah F. Hamm-Alvarez:

Live cell imaging of GFP-Rab11a in lacrimal gland acinar cells reveals distinct vesicle pools. ■

Light Scattering, 20th Annual International Colloquium, October 19-20, 2009, Santa Barbara, California.

Siti Janib, Jenan Abid*, Martha Pastuska and J. Andrew MacKay: The characterization of elastin-like polypeptide (ELP) block copolymers.

*Univ of London. ■

Moving Targets, 8th Annual Multidisciplinary Scientific Symposium, Los Angeles, November 7, 2009.

R.T. Hamilton, J. Hwang, H.N. Hodis*, E. Cadenas: Protein unfoldedlow density lipoproteinregulates mitochondrial

bioenergetics and redox status via c-Jun-n-terminal kinase-2 phosphorylation: Implication for the atherogenic phenotype of coronary artery disease. *KSOM-ARU

S.N. Mohd Janib, J. Abid*, M. Pastuszka and J.A. MacKay: Nanoparticle self-assembly using genetically engineered polypeptides. *Univ of London, School of Pharmacy

Melissa Millard, Divya Pathania, Yumna Shabaik, and Nouri Neamati: Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. ■

The San Antonio Nathan Shock Aging Conference Mayan Ranch, Texas Hill Country, Bandera, Texas, October 2009

R.T. Hamilton, J. Hwang, H.N. Hodis*, E. Cadenas: Protein unfoldedlow density lipoproteinregulates mitochondrial

bioenergetics and redox status via c-Jun-n-terminal kinase-2 phosphorylation: Implication for the atherogenic phenotype of coronary artery disease. *KSOM-ARU. ■

SFN (Society for Neuroscience) Annual Meeting, Chicago IL, October 17, 2009.

Roberta Diaz-Brinton Lab

R. D. Brinton1, J. Wang4, L. Liu1, *Z. Mao2, L. Zhao1, T. E. Morgan3: Progesterone and clinical progestins differentially regulate proliferation of rat neural progenitor cells both in vitro and in vivo. 1USC PPSI, 3Gerontology, 2USC, Los Angeles, CA; 4Pathology, Univ of MS Med Ctr, Jackson, MS

R. D. Brinton1, J. W. Simpkins2, J. H. Morrison3, M. Singh2: Steroid hormone action in the brain: Implications for aging and

neurodegenerative disease. 1USC PPSI, USC, Los Angeles, CA; 2Pharmacol. and Neurosci., Univ North Texas Hlth Sci Ctr, Ft. Worth, TX; 3Fishberg Dept. of Neurosci, Mount Sinai Sch of Med, New York, NY

S. Chen1, J. Wang1,3, R. W. Irwin1, J. Yao1, L. Liu1, R. T. Hamilton1, J. Lemus1, R. D. Brinton1,2:

Allopregnanolone promotes myelin formation associated with decreased accumulation of Amyloid β in the triple transgenic mouse model of Alzheimer's disease. 1USC PPSI, 2Program in Neurosci, USC,3Dept of Pathology, Univ of MS Med Ctr, Jackson, MS

R. T. Hamilton, J. Lemus, E. Agbonwaneten, A. M. Pedroza, A. J. Compadre, J. Yao, R. W. Irwin, S. Chen, R. D. Brinton:

Dysregulation of cholesterol homeostasis in the aging 3xTG mouse: Implication for increased cholesterol turnover, catabolism, and neurodegeneration. USC PPSI

R. W. Irwin1, J. Yao1, S. S. Ahmed1, R. T. Hamilton1, E. Cadenas1, R. D. Brinton1,2:

Impact of progestins on estradiol potentiation of mitochondrial function. 1USC PPSI, 2Programs in Neurosci, USC.

C. Singh1, R. Irwin2, J. Yao2, S. Chen2, L. Liu1, R. F. Thompson1, R. D. Brinton2:

Allopregnanolone enhances learning and memory in adult female triple transgenic Alzheimer’s disease mice. 1Neurosci. Program, USC,2 USC PPSI

L. Liu1, K. E. Mcclure2, L. Zhao2, R. D. Brinton2: Progesterone and clinical progestins differentially regulate proliferation of

rat neural progenitor cells both in vitro and in vivo. 1Dept Neurosci Prgm, 2USC PPSI

F. Ding1, R. Irwin1, J. Yao1, J. Mao1, S. Chen1, R. Park2, G. Dagliyan2, P. Conti2, R. D. Brinton1,3: Ovariectomy induces hypometabolism in normal and transgenic Alzheimer’s mouse brain which is prevented by 17β- estradiol. 1USC PPSI, 2Mol Imaging Ctr,3 Program in Neurosci, USC

(more in p.12)

Brinton Lab at the SFN Annual Meeting. L-R: Ladies, Liqin Zhao, Martha Hernandez, Jennifer Mao, Robbie Brinton, Shuhua Chen, Fan Ding; Gentlemen: Ron Irwin, Ryan Hamilton, Jia Yao.

A trimester publication for the faculty, staff, students, alumni and friends of the Department

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Congratulations

SEMINAR SERIES Shimon Weiss University of California, Los Angeles, Nov 6, 2009 Faculty Host: Julio Camarero Title: Multiscale, Superresolved, Ultrasensitive Optical

Molecular Imaging

Brian M. Stoltz California Institute of Technology, Nov 11, 2009 Faculty Host: Nouri Neamati Title: Complex Natural Products as a Driving Force for

Discovery in Organic Chemistry

Mark R. Kelley Indiana Univ Simon Cancer Center, Dec 4, 2009 Faculty Host: Nouri Neamati Title: The many functions of APE1 as a DNA repair and

redox signaling target for cancer therapeutics and other indications

David H. Thompson Purdue University, Dec 11, 2009 Faculty Host: Andrew MacKay Title: Development of Bioresponsive Materials for Drug

Delivery and Integral Membrane Protein Sensing

Shuibing Chen Harvard Univ, Howard Hughes Med Inst, Dec 3, 2009

Faculty Host: Clay Wang Title: "Manipulating Embryonic Stem Cell Fate using

Chemical Approaches

Qiaobing Xu Massachusetts Inst of Tech, Jan 7, 2010 Faculty Host: Clay Wang Title: Soft Nanotechnology: Functional Nanomaterials

from Top-down Fabrication and Bottom-up Self Assembly

David J. Craik The University of Queensland, Brisbane, Australia, January 13, 2010

Faculty Host: Julio A. Camarero Title: Discovery and applications of cyclic proteins

Bogdan Z. Olenyuk The Univeristy of Arizona, Leon Levy Comprehensive Cancer Center, January 22, 2010

Faculty Host: Clay Wang Title: Control of Transcription and Receptor Function: a

Chemical Perspective ■

Vivian Galicia for winning the 1st prize for her oral presentation entitled, “Activation of Cancer Stem Cells in Hepatic Pten Deficient Mice Requires Liver Injury.”

Ni Zeng for winning the top prize for her poster presentation entitled, “PTEN regulates pancreatic beta cell proliferation and aging process.”

GRADUATE STUDENT SEMINARS James Sanchez October 7, 2009 Advisor: Clay Wang Student Host: Janette Contreras Title: The study of the Aspergillus nidulans metabolome in the

post-genomic era.

Anna Scott October 28, 2009 Advisor: Jean C. Shih Student Host: Liya Xu Title: Developmental and Behavioral Consequences of

Monoamine Oxidase Deficiency

Sean Godar November 18, 2009 Advisor: Jean C. Shih Student Host: Anna Scott Title: Behavioral disinhibition and reduced anxiety-like behaviors

in monoamine oxidase B-deficient mice

Vivian Galicia December 2, 2009 Advisor: Bangyan Stiles Student Host: Sean Godar Title: Activation of cancer stem cells in hepatic Pten deficient

mice requires liver injury.

Maya Popova December 9, 2009 Advisor: Ronald L. Alkana Student Host: Vivian Galicia Title: Sites of Ethanol Action in P2X4 Receptors

Xiaoying Chen January 6, 2009 Advisor: Wei-Chiang Shen Student Host: Jennifer-Ann Bayan Title: Design of in vivo Cleavable and Non-cleavable Linkers for

Recombinant Fusion Proteins

Robert Mo January 20, 2010 Advisor: Wei-Chiang Shen Student Host: Xiaoying Chen Title: "Design of siRNA Polyplex for Enhanced Cellular Uptake."

Yumna Shabaik January 27, 2010 Advisor: Nouri Neamati Student Host: Robert Mo Title: In vitro mechanistic studies of AS421 for the treatment of

pancreatic cancer ■

Jason pictured with his poster presentation at the SFN Annual Meeting in Chicago, Oct 2009.

(L-R) Vivian and Ni with faculty advisor, Bangyan Stiles, shown with Ni’s top-prized poster.

The honors were awarded at the 13th Annual Pathology Conference sponsored by the USC Pathology Department on February 5-6, 2010 at Dana Point, CA. ■

Jason Boyang Wu for successfully defending on October 22, 2009 his dissertation entitled, “Differential Regulation of Monoamine Oxidase A and B Genes.” Faculty mentor is Jean C. Shih. ■

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

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WWhheerree iiss sshhee nnooww?? UPDATE FROM OUR ALUMNA

MMEEII--CCHHIICCHH HHSSUU

I entered USC back in 1982, originally aiming for a

Master's degree. I was fortunate to work in my beloved advisor’s lab, Jean C. Shih, where I would meet Ping, Maria, Dana, and J.D., with whom I developed a close friendship during my stay at USC. To me, Dr. Shih is the most intelligent, considerate, and diligent person I have ever met. I will always remember my shock when I returned to my lab from a lecture one fateful day. I found out that the expensive high-performance liquid chromatography equipment that I was responsible for was damaged due to spilled solvents. Instead of blaming me, Dr. Shih comforted and told me that it was probably an accident; and I happily and gratefully accepted this as an accident, too! Later on, she encouraged me to enter the Ph.D program. I took her suggestion and this decision had changed my whole life; I received my Ph.D degree in Pharmaceutical Sciences at the USC School of Pharmacy in 1986.

Life at USC was full of laughter and tears. On the bright side, throughout my four years working in Dr. Shih's lab, we would have a group meeting discussing our research findings and enjoying savory donuts, which were faithfully provided by Dr. Shih every week. We frequently celebrated the holidays with parties at Dr. Shih’s house or the Cantonese restaurants. Not only that, we often gathered after work, chatted about our families, music, food, and various folk custom cultures. On the dark side, I was obligated to change collection tubes at midnight every so often, even during the weekends. In addition, I would have to visit the slaughterhouse to get bloody beef liver and to wait at the hospital to retrieve some lukewarm human placenta for research purposes. Most of the time, laboratory job was quite miserable, but my lab mates and I looked forward to our brighter future that awaited us beyond this threshold.

After receiving my Ph.D. degree, I worked at the National Laboratory of Food and Drug Bureau,

Department of Health in Taiwan. On February 1994, I started working at the National Taiwan Sport University, where I am currently a professor and chairman of Graduate Institute of Sports Science. In addition, I also held other positions as a medical commissioner of the Taipei Olympic Committee and a commissioner of National Bureau of Controlled Drugs for accreditation of drug-abuse urine-testing laboratories.

Although the research I did for my dissertation concerned with the photoaffinity labeling of beef liver and human placenta monoamine oxidase by 4-fluoro-3-nitrophenyl azide, after receiving my doctorate, my research focused on drug analysis, sports nutrition, and nutritional biochemistry. By utilizing the research method I learned in USC and by using the knowledge acquired from pharmaceutical science, I am able to cross my field of study and integrate it with sports, doping, and nutrition.

As for my personal life, my husband, David C. H. Chen, is a very caring physician with great optimism and humor. We have two children, a daughter (Daphne) and a son (Alexander), who are both currently enrolled at UCSD. Whenever I come to visit my children in California, I will never forget to visit USC and Dr. Shih.

As people say, reminiscence can bring us pleasure. Every year, when I attend my students’ graduation ceremony, I dress up in my USC cap and gown as a reminder that I will forever be a part of the Trojans, with pride, and honor. ■ WALTER WOLF (cont’d from p.6) That coping has been made easier by the pleasure and joy that the activities of my children – Jenny and David – are providing. Jenny, having been in elementary education all her adult life, is now blazing new trails trying to fill unmet needs in the cultural growth of children and young adults. And David, having been a leader in ensuring the rights and the welfare of persons with disabilities at the local level, has now expanded into leading such activities for persons with disabilities at the national and international levels. As a father, as a human being, I feel extremely rewarded to work with my children on being able to develop and implement their dreams. A number of people have urged me to write about my life and what I have done in the past. In line with my motto: “What has been done is interesting, what remains to be done is exciting”, I have chosen to concentrate here on my future goals. ■

Mei-Chich Hsu with husband, David Chen, daughter, Daphne and son, Alexander.

A trimester publication for the faculty, staff, students, alumni and friends of the Department

12

Welcome ~

Rona Ramsay Rona Ramsay is on sabbatical from her position as a professor at the University of St. Andrew's School of Biology where she is a Reader in Biochemistry. She will work in Jean C. Shih's lab from February to April this year to investigate the effect of lack of MAO A and MAO B on the function and proteomics of mitochondria. She is an expert in molecular enzymology and mitochondrial function. Her research commonality with Dr. Shih is understanding the function of MAO and how to modulate it with drugs. (For more on Rona Ramsay, click here). ■

Kristie Kelly Kristie Kelly is the new Research Affairs Program Administrator for the School of Pharmacy. As such she will be assisting the department chair, Sarah Hamm-Alvarez, who is also the Associate Dean for Research Affairs. Kristie joins USC from Caltech, where she worked as the assistant to the Director of the Biological Imaging Center. She has a background in social sciences with some research experience as well as work experience in the legal field. Kristie's office is located in the 7th floor office suite next to Kukla Vera. She can be reached at (323) 442-1737 or kellykri@usc.edu. ■

Development on The Translational Research Lab by Liqin Zhao

The School of Pharmacy Translational Research Lab strives to provide supportive access to up-to-the-date specialized instruments/technologies that facilitate translational research from basic science discoveries into therapeutic development. Since its official starting date on October 1, 2009, the Lab has been successful in fulfilling its mission. In the last three months, 13 PIs/research groups have used the lab generating a total usage of 465 hours. The chargebacks, which are collected every 3 months, are used to offset part of the cost on instrument maintenance and necessary upgrades. For instance, a 384-well plate heat block has recently been added to the Real-Time PCR machine, which will greatly expand the high-throughput capacity for gene-based studies. The lab has also been frequently visited by faculty candidates and outside scholars. Dr. Liqin Zhao supervises/manages the lab and student techs-in-charge, administrates the online scheduler, and coordinates chargebacks. An online scheduler is provided to users as a convenient tool for instrument reservations: http://www.uburst.com/cgi-bin/ureserve/hosted/usc.pl Detailed information on lab resources and operational policies can be found on the Research Affairs page of the School Web Site: http://www.usc.edu/schools/pharmacy/research/translational_lab.html ■

POSTER PRESENTATIONS: Society For Neuroscience (continued from p. 10) Jean C. Shih Lab

Scott AL, Bortolato M, Chen K, Shih JC: Inhibition of nitric oxide synthase attenuates exploratory deficits in monoamine oxidase A and B knockout mice.

Chen K, Hsu W, Palagashvili T, Chen U-B, Tabakoff B, Shih JC: The role of MAO B in brain inflammation and genesis off GABAnergic neuron.

Cheng A1, Scott A2, Ladenheim B3, Chen K2, Ouyang X1, Lathia J1, Mughal M1, Cadet JL3, Shih JC2, Mattson MP1: Reduction of Basal progenitor cells in the dorsal telencephalon of monoamine oxidase deficient neonatal mice. 1NIA-NIH, 2USC PPSI, 3Mol Neuropsychiatry Br, NIDA.

Godar S, Bortolato M, Chen K, Shih JC: MAO B KO mice exhibit novelty seeking and reduced neophobia.

Pakaprot N1, Singh C1, Hui EK2, Chin K2, Shih JC2, Thompson RF1: Deficiency in monoamine oxidase A and B results in enhanced emotional and motor learning. 1USC Neurosci Prog, 2USC PPSI.

Wu B, Chen K, Ma C, Shih JC: Microarray analysis identifies p53 as a potential regulator for monoamine oxidase A.

Bortolato M, Godar SC, Frau R, Burgeno LM, Chen KC, Shih JC: Genetic deficiency of monoamine oxidase results in autistic-like features. ■

Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Newsletter Vol. 5, No. 1 January 2010

13

PPUUBBLLIICCAATTIIOONNSS

RRoonnaalldd AAllkkaannaa

Popova M, Asatryan L, Ostrovskaya O, Wyatt LR, Li K, Alkana RL, Davies DL.A point mutation in the ectodomain-transmembrane 2 interface eliminates the inhibitory effects of ethanol in P2X4 receptors. J Neurochem. 2010 Jan 1;112(1):307-17. PMID: 19878433

RRoobbeerrttaa DDiiaazz--BBrriinnttoonn

Zhao L, Yao J, Mao Z, Chen S, Wang Y, Brinton RD. 17beta-Estradiol regulates insulin-degrading enzyme expression via an ERbeta/PI3-K pathway in hippocampus: Relevance to Alzheimer's prevention. Neurobiol Aging. 2010 Jan 4. [Epub ahead of print] PMID: 20053478

EEnnrriiqquuee CCaaddeennaass

Yap LP, Garcia JV, Han D, Cadenas E. The energy–redox axis in aging and age-related neurodegeneration. Advanced Drug Delivery Reviews, 61(14): 1283-1298, 2009. PMID: 19716388

Ledo A, Barbosa R, Cadenas E, Laranjinha J. Dynamic and interacting profiles of ()NO and O2 in rat hippocampal slices. Free Radic Biol Med. 2010 Jan 25. [Epub ahead of print] PMID: 20100565

Antico Arciuch VG, Galli S, Franco MC, Lam PY, Cadenas E, Carreras MC, Poderoso JJ. Akt1 intramitochondrial cycling is a crucial step in the redox modulation of cell cycle progression. PLoS One. 2009 Oct 21;4(10):e7523. PMID: 19844585

Hamm-Alvarez S, Cadenas E. Mitochondrial medicine and therapeutics, Part II. Preface. Adv Drug Deliv Rev. 2009 Nov 30;61. PMID: 19835920

SSaarraahh HHaammmm--AAllvvaarreezz

Schenke-Layland K, Xie J, Magnusson M, Angelis E, Li X, Wu K, Reinhardt DP, Maclellan WR, Hamm-Alvarez SF. Lymphocytic infiltration leads to degradation of lacrimal gland extracellular matrix structures in NOD mice exhibiting a Sjögren's syndrome-like exocrinopathy. Exp Eye Res. 2010 Feb;90(2):223-237. Epub 2009 Oct 21. PMID: 19852957

Hamm-Alvarez S, Cadenas E. Mitochondrial medicine and therapeutics, Part II. Preface. Adv Drug Deliv Rev. 2009 Nov 30;61. PMID: 19835920

RRaajjiinnddaarr SSoohhaall

Brégère C, Rebrin I, Gallaher TK, Sohal RS. Effects of age and calorie restriction on tryptophan nitration, protein content, and activity of succinyl-CoA:3-ketoacid CoA transferase in rat kidney mitochondria. Free Radic Biol Med. 2010 Feb 15;48(4):609-18. Epub 2009 Dec 16. PMID: 20025965

BBaannggyyaann SSttiilleess

Stiles BL. PI-3-K and AKT: Onto the mitochondria. Advanced Drug Delivery Reviews, 61(14): 1276-1282, 2009 PMID: 19720099

AAnnddrreeww MMaaccKKaayy

Liu W, Mackay JA, Dreher MR, Chen M, McDaniel JR, Simnick AJ, Callahan DJ, Zalutsky MR, Chilkoti A. Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model. J Control Release. 2010 Jan 30. [Epub ahead of print] PMID: 20117157

MacKay JA, Chen M, McDaniel JR, Liu W, Simnick AJ, Chilkoti A. Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumours after a single injection. Nat Mater. 2009 Dec;8(12):993-9. PMID: 19898461

Gao W, Liu W, Mackay JA, Zalutsky MR, Toone EJ, Chilkoti A. In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15231-6. PMID: 19706892

NNoouurrii NNeeaammaattii

Ramkumar K, Serrao E, Odde S, Neamati N. HIV-1 integrase inhibitors: 2007-2008 update. Med Res Rev. 2010 Feb 4. [Epub ahead of print] PMID: 20135632

Yamada R, Kostova MB, Anchoori RK, Xu S, Neamati N, Khan SR. Biological evaluation of paclitaxel-peptide conjugates as a model for MMP2-targeted drug delivery. Cancer Biol Ther. 2010 Feb 16;9(3). PMID: 20023432

Sanam R, Tajne S, Gundla R, Vadivelan S, Machiraju PK, Dayam R, Narasu L, Jagarlapudi S, Neamati N. Combined pharmacophore and structure-guided studies to identify diverse HSP90 inhibitors. J Mol Graph Model. 2010 Feb 26;28(6):472-7. Epub 2009 Nov 24. PMID: 20005756

Ramajayam R, Mahera NB, Neamati N, Yadav MR, Giridhar R. Synthesis and anti-HIV-1 integrase activity of cyano pyrimidinones. Arch Pharm (Weinheim). 2009 Dec;342(12):710-5. PMID: 19899101

JJeeaann SShhiihh

Ou XM, Stockmeier CA, Meltzer HY, Overholser JC, Jurjus GJ, Dieter L, Chen K, Lu D, Johnson C, Youdim MB, Austin MC, Luo J, Sawa A, May W, Shih JC. A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase and Monoamine Oxidase B Cascade in Ethanol-Induced Cellular Damage. Biol Psychiatry. 2009 Dec 18. [Epub ahead of print] PMID: 20022592

Kaludercic N, Takimoto E, Nagayama T, Feng N, Lai EW, Bedja D, Chen K, Gabrielson KL, Blakely RD, Shih JC, Pacak K, Kass DA, Di Lisa F, Paolocci N. Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload. Circ Res. 2010 Jan 8;106(1):193-202. Epub 2009 Nov 12. PMCID: PMC2804073

Yin HS, Chen K, Shih JC, Tien TW. Down-Regulated GABAergic Expression in the Olfactory Bulb Layers of the Mouse Deficient in Monoamine Oxidase B and Administered With Amphetamine. Cell Mol Neurobiol. 2009 Nov 10. [Epub ahead of print] PMID: 19902350

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A trimester publication for the faculty, staff, students, alumni and friends of the Department

Adam Lee Han, born August 25, 2009 at Methodist Hospital in Arcadia, CA, weighing 6 lbs 5 oz. Proud father is DerickHan, who graduated from Dr. Cadenas’ lab, now assistant professor of research at KSOM. Equally proud Mama is Tracy Han.

Argyrios Dean Vaitsos, born January 5, 2010, weighing 7 lbs 11 oz, 20.75” long. Proud parents are Costas and Ruhi Ahmed; she’s a graduate from Dr. Duncan’s lab. Deanie was born one year later to Mommy’s good friend and fellow alumna, Anne-Cecile’s baby, shown on the right.

Madeleine Eleonore VasnierHale, among lobsters on Thanksgiving Day, 2009.

Layla Shen, then and six months later. “Flirty,” said grandma Daisy with much delight. ■

Introducing ~ Remember them?

AAPS Reception“Great discoveries and improvements invariably involve the cooperation of many minds.”

– Sarah Hamm-Alvarez quotes Alexander Graham Bell for the premise of the AAPS reception.

14

Christmas raffle winners

Department Holiday Party, San Antonio Winery

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