20.109(F12) Pre-Proposal: Viral mitigation of insulin resistance

Investigators

• Stanley Gill
• Amy Liu
• T/R 20.109 Lab
• Team Yellow

Title of Proposed Project

Antibody-based Regulation of Resistin Levels through a Synthetic Circuit Injected via Vector Immunoprophylaxis

Project Summary

One of the hallmark characteristics of obesity and Type 2 diabetes is insulin resistance, and data across many papers suggests that a peptide called resistin is responsible for the increase in insulin resistance. Here, we wish to use vectored immunoprophylaxis, a technique that involves gene therapy, to introduce a synthetic biological system which can regulate levels of resistin in the body. When an abnormally high level of resistin is present, the synthetic system will activate expression of the injected gene and induce muscles cells in mice to secrete antibodies targeting resistin, which will hopefully lower insulin resistance and prevent further development of obesity and Type 2 diabetes.

Introduction

Previous research has shown a strong positive correlation between the resistin protein level and insulin resistance, suggesting that high levels of resistin may be the cause of insulin resistance, which also commonly coexists with obesity and Type II diabetes (Steppan 2002, Sanchez-Solana 2012). A previous study by Balazs et al. has also shown that genes encoding for specific antibodies can be injected into the muscle tissue of mice through a technique called vectored immunoprophylaxis (VIP). VIP uses adeno-associated virus to transfer the genes into muscle cells, where the genes can then be expressed and neutralizing antibodies can be secreted into the blood circulation (Balazs 2012). Exploring the possibility of using gene therapy and antibodies to reduce excess levels of resistin in the body may significantly reduce insulin resistance and help elucidate the relationship between between resistin and obesity and Type II diabetes.

References: 1. Balazs, A.B., Chen, J., Hong, C.M., Rao, D.S., Yang, L. and Baltimore, D. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481:81-84 (2012).

2. Steppan, C.M. and Lazar, M.A. Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 13:18–23 (2002).

3. Sanchez-Solana, B., Laborda, J., and Baladron, V. Mouse resistin modulates adipogenesis and glucose uptake in 3T3-L1 preadipocytes through the ROR1 receptor. Mol Endocrinol 26:110-127 (2012).

Your idea

Personal health is of great concern to today's society, especially with regards to people's weight. The rate of Type 2 diabetes in the human population has increased alongside the rate of obesity, and it has been clear for some time that excessive weight gain can lead to insulin resistance, which is a direct cause of Type 2 diabetes. Presently, the accepted methods of prevention and treatment of obesity are maintaining a healthy diet and frequently exercise. Drug based weight-loss methods have not been exhaustively explored; of the drugs that have been explored, very few act directly on the adipose tissues and the products they secrete. Because increased levels of resistin can be found in humans who are insulin resistant and mice become insulin resistant when injected with high levels of resistin, the formation of a new therapy that targets resistin can be beneficial in preventing and/or reducing the degree of insulin resistance in any given individual.

Our experiment aims to test if neutralization of resistin via a humoral response can effectively prevent and treat insulin resistance in mice. This will be done using a synthetically created biological system which will be inserted into muscle cells via vectored immunoprophylaxis. The synthetic system will be self regulating and will turn on only when there is an excess of resistin. When the resistin level reaches a certain threshold, the activated system will induce muscles cells to produce monoclonal antibodies specific for resistin. Then the antibodies will bind to resistin and prevent resistin from binding to one of its downstream effectors (such as the receptor ROR1), which may lead to insulin resistance. Upon introducing the system into mice that already show symptoms similar to Type 2 diabetes, we hope that this potentially long acting therapy will result a decrease in resistin in the blood as well as a decrease in insulin resistance. We will test over long periods of time (up 90 days) to monitor how the resistin levels in the blood change at certain time points after the therapy is introduced. We will also periodically perform insulin tests (inject the mice with insulin and measure how long it takes to return to baseline levels) to get a sense of how resistant the mice are, if at all, to the insulin test while being treated with the synthetic system. If we can confirm that downregulating the activity of resistin reduces the level of resistin in the blood and decreases insulin resistance, there may be potential to apply this therapy to treat obesity and Type 2 diabetes in humans as well.

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