Our main goal is to do a correlative study of genomic instability and telomere length during lung cancer progression, starting from normal lung epithelium to invasive carcinoma. This will allow us to locate the onset of instability and test our hypothesis that genomic instability correlates with telomere critical shortening and is followed by telomerase reactivation.
To this end we will:
1. Refine our image analysis routines for 3D reconstruction of cells and DNA sequences stained by Fluorescence In situ Hybridisation (FISH), and of telomeric repeats using quantitative FISH (QFISH)
2. Measure the levels of genetic instability using thick tissue sections with progressive histological stages of Non Small Cell Carcinomas (Sqamous cell carcinoma and adenocarcinomas): morphologically normal epithelium, hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma. For each type, we will quantify genomic instability using 3D cell-by-cell copy number enumeration of two FISH chromosomal probes in thick sections.
3. Determine telomere length status of each type of tissue using terminal restriction fragment (TRF) analysis and high resolution QFISH telomere detection.
4. Measure telomerase activity in the tissues by quantitative immunhistochemical analysis of the catalytic subunit telomerase reverse transcritptase.
5. Establish a time course of the onset of genomic instability, telomere crisis and telomerase activity during lung cancer progression.
Regarding the goals of the IRG action, this grant would support the applicant 2019; efforts to reintegrate into the European research environment, and to transfer the knowledge acquired in his eight year long stay in the US. This grant would provide support to create collaborations with other groups at the host institution and to establish a real multidisciplinary network of interest on cancer imaging that should increase the level of the European research done in this field.
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