David Cortez, Ph.D.
My laboratory is dedicated to discovering the basic biological processes that govern cell growth and genome stability. Cancer arises as a result of genetic alterations. Cells deploy numerous genome surveillance systems to prevent and repair DNA damage and to coordinate repair with cell cycle transitions. However, cancer cells have lost some of these systems and are genetically unstable. We aim to define the components of genomic surveillance systems and understand how they work in a coordinated manner to prevent cancer by inhibiting the cell cycle, promoting DNA repair, or initiating apoptosis.
The DNA damage response pathway is a signal transduction pathway that functions within the cell nucleus. Proteins involved in these pathways include ATM, ATR, p53, Chk2, Brca1, FancD2, and Blms. Mutations in the genes encoding these proteins are linked to specific cancer predisposition, developmental, and premature aging syndromes. Our primary research goal is to understand how DNA damage response pathways function to maintain genome integrity and prevent cancer.
There are currently four specific focuses in the laboratory:
- How does DNA damage activate the checkpoint kinases ATM and ATR?
- What are the substrates of ATM and ATR that are involved in regulating cell division and DNA replication?
- How is DNA replication regulated to ensure accurate duplication of the genome?
- How does the DNA damage binding protein DDB1 regulate genome stability through ubiquitin-mediated proteolysis?
We use a variety of genetic and biochemical approaches in mammalian and yeast systems. RNA inhibition, gene knockouts, mass spectrometry, and yeast genetics all are employed as needed to understand the basic molecular mechanisms that maintain our genomes. We also collaborate with structural biologists to gain a more detailed understanding of how protein-protein interactions regulate DNA damage responses. An exciting new area of investigation involves the use of genetic screens in vertebrate cells to understand genome maintenance. We believe that our multidisciplinary approach to studying these topics will yield new insights into the molecular basis of cancer and aging.
Michael L. Freeman, Ph.D.
My laboratory focuses on 2 aspects of cancer drug development: 1) Development of efficacious sensitizers of ionizing radiation . 2-Indol-3-yl-methylenequinuclidin-3-ols are being used as the basis for development of novel radiation sensitizers. Defined DNA substrates, cell and animals models are used in the approach to design specific sensitizers. 2) Providing a rationale basis for development of chemoprevention agents. Expression of the genes that encode Phase II detoxification proteins is regulated by the transcription factor Nrf2, which itself is negatively regulated by association to the Cul-3 ubiquitin ligase adaptor protein Keap1. Proteomics, biochemical, biophysical and genetic approaches are used to determine if Keap1's activity is regulated by multiple Cys residues that exhibit differential chemical reactivity, allowing integration of different chemical input signals. Nrf2 also impacts inflammation and pulmonary fibrosis. We are investigating the mechanism by which TGF-beta suppresses Nrf2 signaling, thereby contributing to the development of radiation-induced inflammatory and fibrotic responses.
Thomas E. Yankeelov, PhD.
The long term goal of the Cancer Imaging Group (CIG) at the Vanderbilt University Institute of Imaging Research, is to be an international leader in the development and application of imaging techniques that can be used to quantitatively probe fundamental cancer biology as well to assess and predict the responses of tumors to treatment. CIG researchers currently employ MRI, optical, x-ray radiography and CT, SPECT, PET, and ultrasound to conduct studies in anatomical, physiological, cellular, and molecular imaging of cancer. These approaches are applied in both pre-clinical small animal models of cancer, as well as clinical trials. The CIG places special emphasis is placed on the techniques that readily lend themselves to image co-registration and clinical translation. Thus, we focus much of our effort on MRI, PET, SPECT, CT, and ultrasound to provide quantitative information on status of tumors and their response to treatment. Optical imaging is also used for developing new targeted agents and for high throughput studies. In addition to developing new methods of interrogating tumor characteristics (as our current activities below indicate), we offer a large range of services for external users.