The long term goal of the proposed project is to develop a transgenic rodent wherein activation of apoptosis can be imaged non-invasively. Strict coordination of proliferation and apoptosis is essential for normal physiology. An imbalance in these two opposing processes results in various diseases including AIDS, neurodegenerative disorders (Alzheimer's disease), myelodysplastic syndromes (Aplastic anemia, thalassemia), ischemia/reperfusion injury, cancer and autoimmune disease among others. Objective imaging of apoptosis will be a major advancement not only in the screening and validation of novel therapeutic molecules for the above diseases but also in the evaluation of therapeutic success or failure of current and future therapeutic treatment paradigms. In phase I of this proposal we will construct and test in a tissue culture a recombinant DNA molecule that codes for an inactive luciferase protein which during apoptosis becomes a functional luciferase enzyme thus enabling imaging of apoptosis. The ability to image apoptosis non-invasively and dynamically over time will be an invaluable resource to pharmaceutical companies for in vitro high throughput screening of compounds with pro- and anti-apoptotic activity, but also for target validation in vivo.
Apoptosis has been implicated in a wide variety of human diseases. The development of drugs that specifically target enzymes involved in the apoptotic cascade is a vibrant and dynamic research area. The ability to non-invasively image the effectiveness of these drugs in vivo would be a breakthrough that would have significant market applications.
| Laxman, Bharathi; Hall, Daniel E; Bhojani, Mahaveer Swaroop et al. (2002) Noninvasive real-time imaging of apoptosis. Proc Natl Acad Sci U S A 99:16551-5 |
