FUTURE PLANS
1. Administrative Goals
The DDCD Program has met all of the key goals laid out in the five-year plan outlined in May 2000. They were:
• the planned recruitment of 4 new Program members was fulfilled by addition of 7 recently hired faculty;
• the goals of increasing DDCD Program NCI funding to $1.4 M, and total peer-reviewed funding to $2.8M have each been exceeded by approximately $1 million and
• the goal of obtaining funding for a new training grant in Molecular Toxicology was realized.
As a result of the early success of the original 5-year plan halfway through the period proposed, a new 5-year plan has been developed in response to a mandate by Dr. Torti. This plan, which calls for growth in all DDCD Program activities, and particular emphasis on translational research, was further developed at a recent leadership retreat, and will be implemented over the next several years with expectations of continued growth in productivity and funding. We recognize that our growth in the next funding period may not match that over the past five years, which included most of the NIH doubling period. Nevertheless, we believe that we can realistically achieve our goal of at least 10% increased funding per year not including inflation or new hires, and at least 20% annually if inflation and faculty growth are included.
Targeted recruitment of several new faculty is planned, with the goal of strengthening nascent interactive groups in oxidative stress and DNA damage and repair. Recruitment is ongoing for three new positions, two in the Cancer Biology Department and another in the Radiation Biology section of the Radiation Oncology Department. At least two of these positions are likely to be in the areas of oxidative stress, DNA damage or DNA repair. Other new positions are also committed for recruitment in fiscal years 2006 and 2007. The goal of Dr. Townsend, who interviews all of the candidates for these positions and provides feedback to the CCCWFU leadership and Chairs of the recruiting departments, is to bring in new faculty with research interests that complement the DDCD Program strengths in at least one of the three major areas of focus. Specifically, these are, in order of priority: 1) oxidative stress and oxidant signaling; 2) DNA damage and repair; or 3) carcinogen metabolism and chemoprevention. Similarly, Dr. Townsend will continue to utilize seed grant funding to encourage development of collaborative interactions in these areas, with the ultimate goal of promoting progress toward the development of Program Project grants in these areas of strength.
The Program Leader, Dr. Townsend, will continue to encourage and initiate new research interaction groups. A group has recently formed to develop collaborations in their shared interests in oxidative signaling, mechanisms of intracellular control of redox tone and markers of oxidative stress. This group includes Drs. Leslie Poole, Jacqueline Fetrow, Todd Lowther, Mike Robbins, and Bruce King. Their goals are: 1) to develop and test new analytical approaches to measurement of intracellular redox status, e.g. using novel fluorescent probes that specifically label protein sulfenic acid residues, and 2) to determine the functional significance of antioxidant enzymes and transcriptional regulatory proteins that utilize cysteine-sulfenic acid intermediates as “redox sensors” in their active sites. This group has already succeeded in obtaining NIH and other funding.
Dr. Karin Drotschmann has led the formation of a second research interest group in DNA Damage, Repair, and Mutagenesis that meets monthly to discuss new research, new ideas or occasionally to view a webcast from the NIH DNA repair group at the teleconferencing center. This has attracted several lab groups (Townsend, Drotschmann, Koumenis, Miller, & Perrino), and has spawned a tutorial course that meets weekly for one semester each year.
A third new area of research interaction was recently initiated by Dr. Townsend, with the goal of developing translational research collaborations between basic science and clinical faculty in the area of lung cancer. This was done in response to the expressed interests of several faculty and in recognition of the fact that lung cancer is the most common type of cancer treated at CCCWFU. This is a logical outgrowth of the focus of the DDCD Program on DNA damage, chemical carcinogens, and oxidative stress, since all three factors play a major role in lung cancer etiology and biology. Several meetings have taken place between faculty in Cancer Biology, Biochemistry, Hematology/Oncology, and the Genomics Center, and more are planned.
2. Scientific Goals Several of the collaborative research groups are poised to make major advances in the next several years. Although space precludes adequate discussion of all of them, several can serve as examples:
Clearly, the oxidative damage and signaling regulation group led by Dr. Poole has taken a leadership position in the field of oxidative signaling, and the new probes developed by Dr. King are already yielding excellent results in identification of oxidized proteins separated on 2-D gels. In collaboration with Dr. Fetrow and other experts in computational modeling at Virginia Bioinformatics Institute at Va. Tech, a systems biology model will be developed for intracellular control of redox tone.
A new bitransgenic mouse model with inducible lung-specific expression of a mutant human Ras oncogene has been created and validated in the Miller lab, which develops adenomas but not carcinomas. Recent studies suggest that promotion by the inflammatory agent butylated hydroxytoluene (BHT) may synergize with the mutant Ras expression to drive this model further toward lung carcinoma. This mouse model exhibits a strong suppression of the lung inflammatory response that occurs following BHT treatment coincident with Rasinduction, when pretreated with NSAIDs as chemopreventive agents. This model thus appears to be quite promising for future use in lung cancer chemoprevention studies, and pilot funding has been provided by CCCWFU to further develop this project.
The initial discovery, purification, characterization and cloning of genes that appear to play key roles in DNA replication or repair has vaulted the respective investigators into positions of leadership in their fields. The TREX 3’-exonucleases discovered by Dr. Perrino appear likely to play a role in DNA fidelity, perhaps via mismatch repair, and he will pursue this NIH-funded project in collaboration with Drs. Akman and Drotschmann. In addition, Dr. Drotschmann’s hypothesis that MMR proteins act in apoptotic signaling appears likely to lead to a new understanding of the linkage between the cellular response to DNA damage and control of the decision between continued attempts to repair versus commitment to apoptosis.
Another key gene, DNA quadruplex G4 resolvase, that separates tightly hybridized G-rich 4-stranded DNA structures, was similarly pioneered through purification, characterization and cloning in the Akman and Vaughn labs. This fascinating topologically active protein appears likely to play a key role in replication, and possibly also in RNA processing, meiosis, and perhaps telomere processing.
The recent findings by the Torti group that ferritin is induced by antioxidant chemopreventive agents, and that this leads to attenuation of TNF-induced reactive oxygen species is the first clear demonstration that the iron sequestration function leads to reduced oxidative stress. This result will likely also be proven correct in vivo by studies on the new transgenic mouse with tissue-specific inducible ferritin expression. If so, this will help to further define the role of iron and Fenton chemistry in induction or progression of cancer.
The collaborative efforts toward synthesis and testing of novel chemotherapeutic and chemopreventive agents, and also testing of natural products for chemopreventive activity will likely yield successes that may be translated into preclinical animal testing and clinical trials. The clinical trial to test topical curcumin for cervical neoplasia prevention is an example of the model that will be pursued, translating observations from in vitro studies from the bench to the clinic.