Imaging of Apoptosis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The 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, neurdegenerative 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. We have over the last year of our P20 (pre-ICMIC) award developed a reporter cassette which when transfected into mammalian cells results in a polypeptide that has significantly attenuated levels of reporter activity. When this molecule is being expressed in cells undergoing apoptosis, a caspase (proteases activated during apoptosis) specific cleavage of the reporter gene occurs resulting in activation of the reporter thus enabling imaging of apoptosis. In the present proposal we will optimize this novel molecular construct and conduct in vitro (Specific Aim 1) and in vivo (Specific Aim 2) studies. Finally, a transgenic rodent model will be developed wherein the activation of apoptosis within the skin in response to sunlight can be imaged (Specific Aim 3). The ability to image apoptosis non-invasively and dynamically over time will be an invaluable resource to pharmaceutical industry and scientists for in vitro high throughput screening of compounds with pro- and anti-apoptotic activity and also for target validation in vivo.