2005 Young Investigator Project Abstracts
Oxidative stress, a condition in which harmful chemicals become “activated”, can seriously damage important molecules in human cells. Researchers discovered a molecule, NRF2, which responds to oxidative stress by increasing the number of proteins able to detoxify harmful chemicals. We are interested in NRF2, a positive control protein, because we have discovered a protein (CRIF1) that appears to influence NRF2’s activity in a new way. We will use state-of-the-art methods to: 1) identify interacting CRIF1 and NRF2 molecules and identify the part of NRF2 that binds CRIF1; 2) determine which stage(s) in NRF2 activation is affected by CRIF1; 3) test whether CRIF1 confers cell sensitivity to oxidative stress by the mechanism hypothesized.
An estimated 323,090 new cases of prostate cancer are expected to be diagnosed in 2005, the vast majority of which will be early stage/localized cancer with a 5-year survival rate of almost 100%. Most survivors report the occurrence of treatment-related side effects, particularly urinary, bowel and sexual dysfunction. Although many of these symptoms resolve within 12 months of completing treatment, results from longitudinal studies demonstrate that long-term treatment-related symptoms are common and have an adverse impact on disease-specific function and health-related quality of life (HRQL). The present study will evaluate the symptom and HRQL experience among prostate cancer survivors 12-15 months post-treatment using an automated telephone-assisted symptom monitoring system. Graphic symptom summary reports will display patient responses to clinicians in a simple and easy to interpret format. This study will provide clinicians with a method of symptom assessment that will allow symptom and HRQL information to be easily integrated into routine clinical practice.
Dr. Kitlinska’s research project focuses on the role of neuropeptide Y (NPY) in regulation of neuroblastoma growth. Neuroblastoma is a pediatric tumor developing from neuronal precursors. It is the most common malignant disease of infancy, responsible for approximately 15% of all childhood cancer deaths. Due to their neuronal origin, neuroblastomas synthesize and release proteins normally present in the nerves, such as NPY and its receptors. Recently, Dr. Kitlinska has shown that endogenous NPY released from neuroblastoma cells stimulates their growth. Moreover, the peptide also facilitates formation of the new blood vessels, which provide oxygen and nutrient supply to the growing tumors. Thus, by these two synergistic mechanisms, NPY stimulates growth of neuroblastoma. The goal of the research project funded by American Cancer Society was to determine which NPY receptors mediate its growth-promoting effects in neuroblastomas and establish if blocking these receptors will effectively inhibit tumor growth.
Cyclin Dependent Kinases (CDKs) play a role in regulating the cell cycle. In accord with other research, new small molecule inhibitors of CDK2-cyclin A were sought. Through an assay, compounds structurally related to known CDK2 inhibitors were evaluated for activity. Compounds found to have an inhibitory activity were further evaluated in a tumor cell assay in order to assess the value such an inhibitor has on cell proliferation. Through this search, new inhibitory compounds were found that merit further study.
We proposed that cyclin D1 may integrate cell-cycle progression and/or exit with mitochondrial biogenesis. Known components of the mitochondria-to-nucleus retrograde pathway include CREB, mRpl12, and aconitase. In Drosophila, in which proliferation rates are partially uncoupled from growth, cyclin D1 induces cell size and Hif-1 prolyl hydroxylase (HPH) activity. But in mammalian cells, HPH is not required for proliferation by cyclin D1/Cdk4, mitochondria inhibit HPH hydroxylase and cyclin D1 des not affect cell size. Mitochondria produce ATP, regulate single carbon metabolism, fatty acid metabolism and oxidative glycolysis and are a potential target for cancer therapies. As cyclin D1 is inhibited by differentiation and induced by oncogenes, this new function of cyclin D1 may provide a mechanism by which select oncogenes and growth factors contribute to tumor maintenance.