breeding application for FOTS 19800 and 20025
Purpose: This application regards breeding animals to create the experimental and stock animals required in currently approved and on-going 2 experimental applications: #19800: "Reversing/delaying the age-related switch leading to beta-cell quiescence" and in application #20025: "Improving beta-cell function by drug treatment". These projects aim at determining the role of other endocrine cell populations (glucagon- and somatostatin-producing cells), which will be investigated aiming at find novel ways to lower blood glycemia.
Expected distress for the animals:
We do not foresee additional distress to these animals, except for what is occasionally associated with normal breeding. We will monitor all our breeding pairs to ensure animal well-being.
Expected scientific or societal benefit
As the prevalent forms of diabetes are complex disorders, it remains largely unknown what are the cellular and molecular basis of insulin-producing beta-cell decay. Identifying these processes is a requirement for understanding diabetes onset. The study of other complex disorders, such as Parkinson, strongly benefited from researching their monogenic variants. Our projects aim at characterising the unknown mechanisms governing the decay of beta-cells in monogenic diabetes. This study will provide the first comprehensive cellular and molecular timeline of beta-cell decay as well as systematically define the beta-cell niche in diabetes. As only a limited number of scenarios can be considered for stress-related cell-fate changes, the revealed process of beta-cell failure will be relevant for the complex forms of diabetes. Moreover, our transcriptomic analyses revealed new potential therapeutic targets, currently under validation. Our findings will allow a much more efficient clinical intervention with a greater gain in terms of functionality and health span for patients.
Animals to be used: transgenic mice.
Replacement, reduction and improvement
All experiments that do not require a living organism (metabolism; systemic organ interactions) will be performed in vitro by using patient-derived hiPSC. However, as diabetes is a systemic disease involving several organs, certain in vivo studies are unavoidable. Nevertheless, we will optimise the number of mice necessary for our 2 projects by using common experimental groups, where the same set of collected samples will be processed separately for replying distinct questions, hence halving the number of required animals. Our breeding strategy takes into the consideration the reduction of unwanted transgenic genotypes by optimising the breeding pairs (i.e. using homozygous genitors when the genotyping protocol can separate between heterozygous and homozygous animals). Wherever possible, we will maintain the transgenic lines as homozygous, hence assuring the chance for mice with the desired genotype thus reducing the number of mice sacrificed due to unwanted genotype.
Expected distress for the animals:
We do not foresee additional distress to these animals, except for what is occasionally associated with normal breeding. We will monitor all our breeding pairs to ensure animal well-being.
Expected scientific or societal benefit
As the prevalent forms of diabetes are complex disorders, it remains largely unknown what are the cellular and molecular basis of insulin-producing beta-cell decay. Identifying these processes is a requirement for understanding diabetes onset. The study of other complex disorders, such as Parkinson, strongly benefited from researching their monogenic variants. Our projects aim at characterising the unknown mechanisms governing the decay of beta-cells in monogenic diabetes. This study will provide the first comprehensive cellular and molecular timeline of beta-cell decay as well as systematically define the beta-cell niche in diabetes. As only a limited number of scenarios can be considered for stress-related cell-fate changes, the revealed process of beta-cell failure will be relevant for the complex forms of diabetes. Moreover, our transcriptomic analyses revealed new potential therapeutic targets, currently under validation. Our findings will allow a much more efficient clinical intervention with a greater gain in terms of functionality and health span for patients.
Animals to be used: transgenic mice.
Replacement, reduction and improvement
All experiments that do not require a living organism (metabolism; systemic organ interactions) will be performed in vitro by using patient-derived hiPSC. However, as diabetes is a systemic disease involving several organs, certain in vivo studies are unavoidable. Nevertheless, we will optimise the number of mice necessary for our 2 projects by using common experimental groups, where the same set of collected samples will be processed separately for replying distinct questions, hence halving the number of required animals. Our breeding strategy takes into the consideration the reduction of unwanted transgenic genotypes by optimising the breeding pairs (i.e. using homozygous genitors when the genotyping protocol can separate between heterozygous and homozygous animals). Wherever possible, we will maintain the transgenic lines as homozygous, hence assuring the chance for mice with the desired genotype thus reducing the number of mice sacrificed due to unwanted genotype.