Tao, Ya-Xiong , PhD
Rescue of intracellularly retained human melanocortin-4 receptor mutants
General Research Subject: Obesity
Focus: Integrated Physiology\Regulation of Food Intake, Obesity\Animal Models, Signal Transduction (Non-Insulin Action)\Hormones
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Diabetes Type: Type 2 diabetes
Obesity is a significant cause of type 2 diabetes mellitus. Current therapies for obesity are ineffective or associated with significant side effects. Effective therapeutic approaches for obesity are urgently needed. Melanocortin-4 receptor (MC4R) is a critical regulator of food intake and energy expend+W5iture in humans. Mutations in the MC4R gene are the most common monogenic form of obesity. The majority of the mutations in the MC4R gene cause the mutant protein not transported to its correction location, the cell surface. We propose to test the potential of small molecule compounds in correcting this defect. This is the first step towards personalized medicine in treating the patients with these mutations.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and or/curing diabetes?
Obesity is a significant risk factor for type II diabetes. We study obesity caused by mutations in a single gene, the melanocortin-4 receptor (MC4R). Previous studies by us and other investigators showed that the most common defect caused by mutations in this gene is that the mutant protein cannot reach its normal destination, the plasma membrane. We were the first to show that small molecule ligands for the receptor can be used to correct this defect in vitro in heterologous cells. Other investigators have since confirmed our results. The support of this ADA grant will allow us to extend our studies in neuronal cells and in vivo in mice. The long-term goal of our project is to provide personalized treatments for patients with MC4R mutations. Importantly, because we and others showed that these small molecule ligands can also increase the plasma membrane expression of normal MC4R, our studies will likely be also relevant for obese patients without MC4R pmutations. Developing novel therapeutic approaches will have significant impact on preventing type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The current obesity epidemic is directly fueling the diabetes epidemic. Our research will help with diabetes prevention by identifying novel ways to treat obesity.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
When I was 12 years old, my father died of hypertension. Therefore I was always interested in learning about cardiovascular disease. Now we know that obesity, type 2 diabetes, hypertension, and cardiovascular disease are all closely associated disorders. The ADA award will sustain our research efforts in gaining a better understanding of obesity pathogenesis and treatment.
In what direction do you see the future of diabetes research going?
Although it is well accepted that obesity is a significant risk factor for type 2 diabetes, how obesity causes insulin resistance and type 2 diabetes is still not clear. Translating the significant advances in our understanding of obesity pathogenesis into novel effective treatments for obesity will also significantly stem the further increase in diabetes prevalence.
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