Role of Ntrk1 in the development/progression of myeloproliferative neoplasms
Myeloproliferative neoplasms (MPN) are chronic blood cancers whose main complication is development of secondary acute myeloid leukemia. This is a deadly disease, affecting mainly elderly people and particularly challenging to treat. Using a cohort of more than 500 patients, we have discovered a mutation that is enriched in patients of MPN, in both its sporadic and familial forms. These patients also show the most frequent mutations that originate MPN, so we hypothesize that the mutation that we have discovered predisposes to MPN. Thus, the results of this work may lead to advances in knowledge of MPN acquisition, prevention and treatment in patients.
To determine the validity of our hypothesis, we will use a total of 825 mice both females and males with different genetic backgrounds including transgenic mice that have one of the most frequent mutations that causes MPN in humans as well as heterozygous mice for the new mutation that we have discovered, among others. We will perform studies on primary mutants and under transplantations, which will allow to assess if our hypothesis is correct.
To better mimic MPN as an age-associated disease, we will need to study old mice that will be scored with a sheet particularly designed for geriatric mice. Given that some mice will be used for transplantation experiments, the whole project is classified as severe. In these experiments, mice will be irradiated prior to the transplantation to ensure that all the blood-forming cells in the bone marrow are eradicated and will be replaced by the transplanted stem cells. This process may cause a temporary body weight loss. Before starting any additional procedure, we will let mice recover and we will establish cut-off body weight loss parameters to ensure that the animals are in healthy shape for the experiment. During 21 days after transplant, mice will be daily scored with a specific score sheet.
This study must be carried on in vivo, due to the insufficient knowledge of composition of the bone marrow responsible for the support of blood formation and the absence of in vitro alternatives. We will keep the number of animals to a minimum consistent with the obtention of statistically meaningful results, using the mice in the most efficient way possible.
To determine the validity of our hypothesis, we will use a total of 825 mice both females and males with different genetic backgrounds including transgenic mice that have one of the most frequent mutations that causes MPN in humans as well as heterozygous mice for the new mutation that we have discovered, among others. We will perform studies on primary mutants and under transplantations, which will allow to assess if our hypothesis is correct.
To better mimic MPN as an age-associated disease, we will need to study old mice that will be scored with a sheet particularly designed for geriatric mice. Given that some mice will be used for transplantation experiments, the whole project is classified as severe. In these experiments, mice will be irradiated prior to the transplantation to ensure that all the blood-forming cells in the bone marrow are eradicated and will be replaced by the transplanted stem cells. This process may cause a temporary body weight loss. Before starting any additional procedure, we will let mice recover and we will establish cut-off body weight loss parameters to ensure that the animals are in healthy shape for the experiment. During 21 days after transplant, mice will be daily scored with a specific score sheet.
This study must be carried on in vivo, due to the insufficient knowledge of composition of the bone marrow responsible for the support of blood formation and the absence of in vitro alternatives. We will keep the number of animals to a minimum consistent with the obtention of statistically meaningful results, using the mice in the most efficient way possible.