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Revision as of 03:07, 21 October 2017
Background
Obesity problem has become increasingly disturbing these years and arouses widespread concern. Causing terrible diseases like diabetes and certain types of cancer, obesity takes a major toll on human health worldwide. Traditional methods to lose weight are either easy to rebound or associated with side effects, and a perfect treatment of obesity has not appeared yet so far. The goal of our project is to develop a new strategy to treat obesity, with building a transplantable system targeting a specific molecule that functions in white fat tissues.
Given that the reason for fat accumulation lays in both the large number and volume of adipocytes, inducing the apoptosis of adipocytes and white fat tissues would theoretically have therapeutic value in the treatment of obesity. It is known to us that BCL-2 protein inhibits the activity of pro-apoptotic proteins in adipocytes and therefore inhibits adipocyte apoptosis. Thus, this project selected BCL-2 gene as a therapeutic target for the treatment of obesity and for the prevention of a relapse of obesity.
siRNAs are emerging as promising therapeutic drugs against a wide array of diseases. The key obstacle for successful clinical application of siRNA is to develop a safe and effective delivery system directed at the target tissues only. Current techniques for small RNA transfer use viruses or synthetic agents as delivery vehicles. The replacement of these delivery vehicles with a low toxicity and high target-specific approach is essential for making siRNA therapy feasible. Because exosomes have the intrinsic ability to traverse biological barriers and to naturally transport functional small RNAs between cells, exosomes potentially represent a novel and exciting delivery vehicle for the field of siRNA therapy. As therapeutic delivery agents, exosomes will potentially be better tolerated by the immune system because they are natural nanocarriers derived from endogenous cells. Furthermore, exosomes derived from cells engineered to express siRNAs and surface proteins may be capable of delivering these small RNAs to the target cells. Thus, exosome-based delivery of siRNAs may provide an untapped source of effective delivery strategy to overcome impediments such as inefficiency, unspecificity and immunogenic reactions.
In iGEM 2017, NJU-China designed a part (BBa_K1180002???) coding the adipocyte-targeting tPep-Lamp2b fusion protein. We just got some preliminary data both in vitro and in vivo proving that tPep-exosomes can be delivered into the fat tissues located in groin and back in the first half of this year. In recent months, we have tested the function of this parts in detail and entered the experiment data in in the part's page on the Registry.
We employed HEK 293 cells as donor cells to acquire exosomes expressing tPep-Lamp2b fusion protein on the surface. Then we modified our exosome with such peptide to act as white-fat-tissue-specific targeting tool. The siRNA will function to bring out the apoptosis of fat tissue. Our validation experiments were carried out at the level of cells and animals (mice), proving both the targeting and function of siRNA. Eventually, we saw a specific accumulation of the siRNA in the mice’s white fat tissue, which caused obvious adipocyte apoptosis. And therefore we observed the decrease of mice’s fat and weights. This project may successfully provide new insights into future treatment of obesity.
Design
Obesity problem has become increasingly disturbing these years and arouses widespread concern. Causing terrible diseases like diabetes and certain types of cancer, obesity takes a major toll on human health worldwide. Traditional methods to lose weight are either easy to rebound or associated with side effects, and a perfect treatment of obesity has not appeared yet so far. The goal of our project is to develop a new strategy to treat obesity, with building a transplantable system targeting a specific molecule that functions in white fat tissues.
Given that the reason for fat accumulation lays in both the large number and volume of adipocytes, inducing the apoptosis of adipocytes and white fat tissues would theoretically have therapeutic value in the treatment of obesity. It is known to us that BCL-2 protein inhibits the activity of pro-apoptotic proteins in adipocytes and therefore inhibits adipocyte apoptosis. Thus, this project selected BCL-2 gene as a therapeutic target for the treatment of obesity and for the prevention of a relapse of obesity.
siRNAs are emerging as promising therapeutic drugs against a wide array of diseases. The key obstacle for successful clinical application of siRNA is to develop a safe and effective delivery system directed at the target tissues only. Current techniques for small RNA transfer use viruses or synthetic agents as delivery vehicles. The replacement of these delivery vehicles with a low toxicity and high target-specific approach is essential for making siRNA therapy feasible. Because exosomes have the intrinsic ability to traverse biological barriers and to naturally transport functional small RNAs between cells, exosomes potentially represent a novel and exciting delivery vehicle for the field of siRNA therapy. As therapeutic delivery agents, exosomes will potentially be better tolerated by the immune system because they are natural nanocarriers derived from endogenous cells. Furthermore, exosomes derived from cells engineered to express siRNAs and surface proteins may be capable of delivering these small RNAs to the target cells. Thus, exosome-based delivery of siRNAs may provide an untapped source of effective delivery strategy to overcome impediments such as inefficiency, unspecificity and immunogenic reactions.
In iGEM 2017, NJU-China designed a part (BBa_K1180002???) coding the adipocyte-targeting tPep-Lamp2b fusion protein. We just got some preliminary data both in vitro and in vivo proving that tPep-exosomes can be delivered into the fat tissues located in groin and back in the first half of this year. In recent months, we have tested the function of this parts in detail and entered the experiment data in in the part's page on the Registry.
We employed HEK 293 cells as donor cells to acquire exosomes expressing tPep-Lamp2b fusion protein on the surface. Then we modified our exosome with such peptide to act as white-fat-tissue-specific targeting tool. The siRNA will function to bring out the apoptosis of fat tissue. Our validation experiments were carried out at the level of cells and animals (mice), proving both the targeting and function of siRNA. Eventually, we saw a specific accumulation of the siRNA in the mice’s white fat tissue, which caused obvious adipocyte apoptosis. And therefore we observed the decrease of mice’s fat and weights. This project may successfully provide new insights into future treatment of obesity.
INTERLAB
