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Förslaget inkom 2005-01-19

DNA-repair proteins that recognize damage induced by ultrasound

The aim of this project will be to elucidate the repair mechanisms of ultrasound-induced DNA damage.

Effective and correct DNA repair is crucial for the cell survival. In radiation therapy cells are killed mainly by DNA damage. The mechanisms for the induction, recognition and repair of different radiation-induced DNA damage have been intensively studied, which is not the case with ultrasound-induced DNA damage.
Ultrasound is widely used in many different medical fields e.g. diagnostics, physiotherapy, kidney ¿ and gallstone treatment, tissue ablation, hyperthermia production. In the last few years the research fields of possible applications of high-intensity ultrasound has been increasing steadily, not only for tumour treatment but also for other medical purposes e.g. enhanced gene delivery, ablation of cancer tissue, coagulation of bleeding tissue, revascularization of occluded blood vessels, increased drug delivery, ultrasound-activated drug delivery.
Ultrasound has the potential to be a suitable tool for tumour treatment due to its qualities such as non-invasiveness, deep penetration in tissue, and being able to focus in a defined tumour volume.
Ultrasound, of varying physical properties e.g. intensities, frequencies and mode, has been shown to induce cell lysis, loss of cell viability, membrane damage (both reversible and irreversible membrane permeabilisation, lipid peroxidation, removal of cell surface receptors), necrosis, apoptosis, reduced clonogenic cell survival. The molecular mechanisms of cell killing by ultrasound are largely unknown: there are few reports on levels of proteins, mRNAs and gene expression. It has also been shown that ultrasound induces DNA damage, both single- and double strand breaks (DSBs).
DSBs are the most lethal form of DNA damage. They may occur in response to ionizing radiation or to certain chemotherapeutic drugs. DSBs also arise as a consequence of normal cellular metabolism and as consequence of natural processes such as V(D)J recombination (process for generating diversity of antigen-binding proteins, T cell receptors and immunogobulins during lymphogenesis). If not repaired prior to DNA replication or mitosis, DSBs can induce cell death. If misrepaired, DSBs can lead to chromosomal translocations, genomic instability and cancer development.

Working plan
We will start from the start that is from searching for those repair proteins that specifically sense for this kind of DNA damage. Data from our laboratory point to two candidates. These are large proteins, ataxia-telangiectasia (ATM) and/or DNA-dependent protein kinase (DNA-PK), that initiate two major repair pathways of ionizing radiation-induced double strand breaks. So two things will be studied: whether ultrasound induces expression of ATM and DNA-PK and the DNA binding capacity of these proteins. Also, it will be of great interest to compare the ultrasound-induced repair mechanisms with those involved in the repair after exposure to other DNA damaging agents such as ionizing radiation. In this work different biochemical methods will be used: Western blot, immunoprecipitation and protein activity assays.

The work will be performed at the unit of Medical Radiation Biology, Department of Oncology-Pathology, Karolinska Institutet. Our lab is located at Cancer Centrum Karolinska, Karolinska Hospital.


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