Highlights
Research | Outreach and Education | Administrative
Research Highlights
Non-B DNA-Forming Sequences: Hotspots of Genetic Instability in Mice
Drs. Karen Vasquez and John DiGiovanni are collaborating on studies to determine the role DNA structure may have in chromosome breakage and rearrangements. Noncanonical DNA structures are postulated to be responsible for some breakpoint hotspots that occur frequently in cancers. To further study this hypothesis and to explore the possibility that environmental agents may influence stability at these sequences, a novel transgenic mouse model was developed to detect DNA structure-induced chromosome breakage, deletion, and rearrangement events from sequences that map to break points in leukemia and lymphoma patients. Large-scale chromosomal deletions and/or translocations occurred in 5 of the 65 mice carrying the H-DNA-forming sequences and in 7 of the 106 mice carrying the Z-DNA-forming sequences, but in 0 of the 63 control mice. These data provide the first evidence that H-DNA- and Z-DNA-forming sequences can lead to genetic instability in a chromosomal context in living organisms. In addition, these results suggest that helical distortions can result in spontaneous chromosome breakage and the translocation of genes involved in human disease, including cancer. This model should prove useful to further understanding of the mechanisms that are involved in disease etiology, including cancer and the role that environmental agents play in this process.
A Pilot Project was awarded to Drs. Vasquez and DiGiovanni in 2008 to begin exploring the interactions between environmental agents and Non B DNA structures. Some of their recent findings have also been reported in Wang et al. Furthermore, these studies are being aided by the Molecular Biology Facility Core.
- Wang G, Carbajal S, Vijg J, DiGiovanni J, Vasquez KM. DNA structure-induced genomic instability in vivo. J Natl Cancer Inst 100(24):1815-7, 2008.
The p53 R72P Polymorphism: Linking Mouse Models to Human Studies
Drs. David Johnson, Qingyi Wei, and Sara Strom collaborated on a CRED-funded pilot project (funded in 2007) that led to the award of an NIEHS R01 grant on which Dr. Johnson is P.I. and Dr. Wei is a Co-Investigator. In this work, the role of specific polymorphisms in the p53 gene are being studied.
The human p53 gene, which plays a critical role in response to many cellular stresses, contains a common polymorphism that results in either an arginine (R) or proline (P) residue at position 72 of the p53 protein. Numerous epidemiological studies have associated this polymorphism with risk for developing various cancers and other diseases. However, different genotypes are associated with a predisposition for developing different cancers and in some cases there is conflicting data. Dr. Johnson generated mice homologous for either the p53R (p53R/R) or p53P (p53P/P) allele. To examine the apoptotic activities of the humanized p53 variants, p53R/R and p53P/P mice in the SKH hairless strain background, together with wild type controls, were exposed to UV radiation. Examination of immunostained skin samples revealed that homozygous p53R/R mice had significantly increased numbers of apoptotic epidermal keratinocytes compared to either wild type or p53P/P mice. To further confirm the functional difference between the p53R and p53P variants, homozygous p53P/P and p53R/R mice along with wild type controls were exposed to ionizing radiation (IR). Similar to UV irradiated skin, mice expressing the p53R variant had higher numbers of apoptotic cells than mice expressing p53P following IR treatment. Apoptotic response was also examined in intestinal tissue. p53R/R and wild type mice showed a similar apoptotic response to IR, while p53P/P mice had a lower apoptotic response. Thus, while the same functional difference in apoptotic capacity is observed in the different tissues, p53R appears to be hyperactive in the skin while p53P is hypoactive in the intestine compared to wild type murine p53. Data from these mouse model studies is now being used to further develop and test new hypotheses on the role of this p53 polymorphism in human health and disease through access to human populations in collaboration with Dr. Wei.
The Molecular Biology Facility Core and the Histology and Tissue Processing Core provided essential services to these studies. It is anticipated that the Integrative Health Sciences Facility Core (IHSFC) will aid in ongoing, and future studies.
The Role of Dietary Energy Balance in Modulating Cancer Risk
A number of Center investigators have ongoing research in the area of dietary energy balance and its relationship to cancer risk and progression. Recent epidemiological studies have suggested that diet plays a major role in the etiology of cancer. Furthermore, numerous investigations have shown that nutrients and other dietary constituents may alter the incidence of tumors in a variety of epithelial tissues, including the skin, lung, bladder, breast, pancreas, colon and liver, by modulating either the initiation and/or promotion stages of carcinogenesis.
Drs. Susan Fischer and Stephen Hursting determined that dietary energy balance impacts spontaneous pancreatic lesions in the K5.COX-2 transgenic model of pancreatic cancer. With findings presented at the 2008 AACR Annual Meeting, Drs. Fischer and Hursting found that prevention of weight gain with a restricted calorie diet sharply reduced the development of pancreatic lesions in a transgenic strain of mice that spontaneously develops pancreatitis that leads to pancreatic adenocarcinoma. This study sheds light on the connection between obesity, calorie intake and pancreatic cancer by comparing a calorie restricted diet, an overweight diet and an obesity-inducing diet in these mice.
In other studies, Dr. Stephen Hursting collaborated with Drs. John DiGiovanni and Sara Strom in determining that dietary energy balance modulates signaling through Akt/mTOR pathways in multiple epithelial tissues. A restricted calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of these two signaling pathways known to contribute to cancer growth and development. An obesity-inducing diet, by contrast, activated those pathways. These findings provide the basis for future translational studies through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans.
Drs. Strom and DiGiovanni also collaborated with Dr. Michele Forman to investigate the role that dietary fat intake plays in modulating obesity-related prostate cancer progression (assessed by biochemical failure that occurs after treatment for localized prostate cancer). With their findings reported in Strom et al, they found that men who consumed high-saturated fat diets were more likely to experience biochemical failure and had significantly shorter biochemical-failure-free-survival than men with low saturated fat diets. Understanding the interplay between modifiable factors, such as diet and obesity, and disease characteristics may lead to the development of behavioral and/or targeted interventions for patients at increased risk of tumor initiation and progression.
The studies described above benefited from services provided by the Molecular Biology Facility Core, the Histology and Tissue Processing Facility Core and the Integrative Health Sciences Facility Core. Publications resulting from Center support include:
Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD, DiGiovanni J. Dietary Energy Balance Modulates Signaling through the Akt/Mammalian Target of Rapamycin Pathways in multiple Epithelial Tissues. Cancer Prev Res 1(1), 65-76, 2008.
- Moore T, Carbajal S, Beltran L, Perkins SN, Yakar S, Leroith D, Hursting SD, Digiovanni J. Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels, Cancer Res, 68 (10), 3680-8, 2008.
Strom SS, Yamamura Y, Forman MR, Pettaway CA, Barrera SL, DiGiovanni J. Saturated fat intake predicts biochemical failure after prostatectomy, Int J Cancer, 122 (11), 2581-5, 2008.
Dietary Magnesium and DNA Repair Capacity as Risk Factors for Lung Cancer
Drs. Somdat Mahabir, Qingyi Wei, Carol Etzel, Margaret Spitz, and Michelle Forman collaborated on a lung cancer case-control study to increase understanding of the relationship between dietary magnesium (Mg) and lung cancer. Results of this study were published in Mahabir et al, 2008. These studies were benefited by access to the Integrative Health Sciences Facility Core.
Dietary minerals in lung cancer risk remain an understudied area of research. Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case-control study, CRED investigators identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83-3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing findings suggest that Mg from food sources in the typical USA diet offers protection against lung cancer and that Mg intake and DRC together modulate risk. Further studies to assess the role of Mg intake and tissue levels and lung cancer mortality could complete the evidence-based research picture for this essential mineral.
- Mahabir S, Wei Q, Barrera SL, Dong YQ, Etzel CJ, Spitz MR, Forman MR. Dietary magnesium and DNA repair capacity as risk factors for lung cancer. Carcinogenesis, 29 (5), 949-56, 2008.
Outreach and Education Highlights
Community Science Night Focuses on Nutrition and UV Exposure
To enhance scientific literacy and public understanding of current research discoveries, COEC sponsored the first semiannual Community Science Night (CSN Live) on May 22, 2008, at the Smithville Recreation Center. Over 130 people, including community residents, students, teachers and parents attended. CSN Live is a component of the CENTIPEDe (Community Education Networks To Integrate Prevention of Environmental Disease) Project, supported by the HHMI. The first CSN Live featured guest speakers from the CRED, as well as scientific demonstrations by students and Center staff. Dr. Steve Hursting, CRED member at the University of Texas at Austin, spoke about the correlation between nutrition and disease. SPRD scientist and CRED member, Dr. David Mitchell, described the correlation between UV-induced DNA damage and skin cancer and the importance of safety measures to avoid over-exposure. Each scientist responded to questions from the audience, in an open question and answer session lasting over 45 minutes. Audience members lined up to ask the experts about cancer research, risks, cures, treatments and other issues related to environmental health and disease. The ultimate goal of all of these activities is to promote healthy lifestyle choices, to increase community scientific literacy, and to stimulate interest in environmental health science research careers and discoveries.
Summer InstituteSummer Institute is an annual, five-day teacher professional development conference that introduces new curricular materials and pedagogy to teachers throughout the state of Texas. Started in 2001 with only 44 participants, the 8th annual Summer Institute in 2008 attracted 217 teachers from the state of Texas. The institute includes daylong workshops that explore the critical interrelationships between human health and the environment. Institute workshops feature educational materials and curricula developed by some of the nation’s finest research institutions, including the NIH, Baylor College of Medicine, The National Center for Atmospheric Research (NCAR), Texas A&M University and many others. This year, workshops included “Regenerative Medicine”, “Cell Biology and Cancer,” “Science Court,” “Backyard Bloodsuckers” and “Rural Schools Initiative.” The Rural Schools Initiative is a new workshop that focuses on novel, low cost, environmental field experience venues that are available in rural areas and can provide high quality, “real-world” learning for students. Workshops are facilitated by curriculum developers, classroom teachers and scientists and include explorations of content information, review of new and exciting lesson and activity plans, demonstrations and hands-on activities that can be immediately translated to classroom use. The trainers also provide valuable information on different pedagogical approaches and strategies to address the education needs of a variety of different learners, including those in special education programs. Over 30% of all SI trainers are active research scientists, thus stimulating interactions between scientists and teachers and also encouraging a direct translation of cutting-edge research to classroom learning.
Attendees’ comments from the 2008 Summer Institute will influence the design of the 2009 workshop, which will feature representatives from a variety of rural health, technical and technological employers, including regional health care facilities, veterinary clinics, surface and waste water treatment plants and landfills. The goal will be for representatives to discuss the educational requirements for positions at their facilities and to inform teachers about technical employment opportunities for rural students. The teachers will also have the opportunity to visit these facilities and investigate them as possible field experience venues for their students. Development of inquiry based lesson and activity plans based on the skills needed for these positions will be provided in the workshop.
Summer Undergraduate Research ProgramThe Summer Undergraduate Research Program (SURP) provides an opportunity for college students to get hands-on experience in a basic biomedical research laboratory. This highly successful program routinely receives an average of 114 applications for 12-20 slots. During the 10-week summer internship, students participate in hypothesis-driven, project-based investigations under the direction of training faculty mentors. Students come from all over the country to participate in hands-on environmental health science bench research. It is not uncommon for SURP students to make substantial contributions to research programs and to earn co-authorships on scientific abstracts and occasionally, on manuscripts. Since 1996, 225 students have participated in SURP and 93% of the students have gone on to pursue post-graduate education in science and/or medicine or to begin scientific or health-related careers.
The 2008 Summer Undergraduate Research Program (SURP) and High School Research Program (HSRP) included 21 students, including one Public Health intern, who participated in environmental health science research under the directions of CRED faculty on 3 campuses, Science Park Research Division and Veterinary Sciences Division of MDACC and the Department of Pharmacy at UT Austin. Students also attended a field experience at the main campus of The University of Texas M.D. Anderson Cancer Center in Houston, Texas and at the Michael E. Keeling Center for Comparative Medicine and Research in Bastrop, Texas. These field experiences provide the students with a better perspective of the continuum of basic, translational and clinical EHS research and career opportunities.
Hispanic Engineering Science and Technology WeekAs part of Center’s goal to enhance scientific literacy in minority communities and to recruit minority students into science careers, CRED scientists, Dr. Robin Fuchs-Young and Dr. Irma Gimenez-Conti, attended the 2008 HESTEC (Hispanic Engineering, Science and Technology) Week at the University of Texas-Pan American. HESTEC was started seven years ago at UT Pan-Am, one of the country's top Hispanic serving institutions, to address the critical shortage of minority scientists and engineers in the United States. Drs. Gimenez-Conti and Fuchs-Young presented talks on "Biomedical Research and Challenges to Society" at the Science Symposium and discussed environmental health science research careers with undergraduate students and faculty.
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Annual Retreat
The Center retreat was held October 23rd & 24th , 2008. The focus of this years retreat was on science and included a Keynote address from Dr. Christopher Austin, Director of the NIH Chemical Genomics Center, and Senior Advisor for Translational Research at NHGRI. In an effort to maximize scientific interactions, CRED members were encouraged to sponsor an individual from their laboratory to present a scientific poster allowing participants to gather for the discussion of exciting research and future goals for the Center. Both days included informative presentations by Center Members highlighting current work across all four Research Focus Areas. A workshop on “Small molecule Screening Approaches in Drug Development and Biological Research” was co-moderated by Dr. Mark Bedford (M. D. Anderson Cancer Center, SPRD), Dr. Michael Mancini (Baylor College of Medicine) and Dr. Christopher Austin (NIH). Finally, representatives from each Facility Core displayed posters during a poster session to end the retreat providing individual consultations to CRED members.
External Science Advisory Board VisitThe ESAB met at the Smithville campus on September 23, 2008. During this one-day meeting ESAB members were given an overview of the CRED, current research highlights, presentations from the Career Development Program, Community Outreach and Education Core, Facility Cores and a poster session highlighting past pilot project awardees. Following the meeting the ESAB provided a written report, including specific comments and recommendations regarding the CRED components to Dr. DiGiovanni.
DNA Repair SymposiaA DNA Repair Mini-Symposium was held on February 29 and March 1, 2008 in Round Top, Texas. This mini-symposium focused on the general area of DNA repair and included a variety of topics ranging from DNA damage response to mechanisms of genomic stability/instability. The meeting format provided a great opportunity to disseminate new scientific ideas and results of mutual interest to DNA repair researchers within our institution. Dr. Sam Wilson, Acting Director of the NIEHS and Chief of the DNA Repair & Nucleic Acid Enzymology Section gave the keynote address.
Career Development Program WorkshopsThe CDP has initiated a series of planned activities aimed at cross training basic, clinical and translational researchers, stimulating collaborative research projects involving researchers in these disciplines and enhancing the progress of new and transitioning investigators. In addition to the Molecular Biology Workshop and Biostatistics Workshop sponsored by the CDP in 2007, the CDP held another Molecular Biology Facility Core workshop on July 3, 2008 at Science Park – Research Division, Harrison Auditorium with the goal of enhancing transdisciplinary research skills in young investigators. This two-hour workshop was designed to familiarize participants with the basic techniques of molecular and cellular biology and biochemistry that are being applied to cutting edge research in the fields of environmental medicine, toxicology, molecular epidemiology, nutrition, chemoprevention, and translational research. Approximately 30 scientists from the SPRD campus attended the workshop.
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