Chazin, Walter J, PhD
A fragment-based approach to identify inhibitors of the receptor for advanced glycation end product signaling
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Phosphatases-Kinases
Type of Grant: Innovation
Project Start Date: January 1, 2013
Project End Date: December 31, 2014
Diabetes Type: Type 1 diabetes
Diabetic patients are at increased risk for developing circulatory diseases. In particular, accelerated atherosclerosis, or hardening of the arteries is a major cause of death in patients with diabetes. Despite a wealth of information, further research is necessary in order to understand the causes of complications resulting from diabetes. There is a direct correlation with accelerated atherosclerosis and accumulation of sugar-modified proteins that result from hyperglycemia. Sugar modified proteins trigger an inflammatory response from a molecule called RAGE.
This research proposes a novel approach to generate chemicals that can be used to block RAGE in order to 1) further understand the basic biology underlying the complications associated with diabetes; and 2) to be tested as possible drugs for the treatment of atherosclerosis.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
Diabetics suffer from not being able to properly breakdown sugars. One of the by-products of this problem is the formation of unusual modifications of proteins and lipids, which are termed advanced glycation end products (AGEs). The rate of formation of AGEs has been directly correlated to the level of blood glucose. The presence of AGEs in the bloodstream is dangerous because they serve as general signals for inflammation of tissues, even when inflammation is not needed. A specific connection to AGEs has been established for atherosclerosis, hypertension, renal damage, cataracts, neuropathy and other problems encountered by persons with diabetes. The effects caused by AGEs arise because they interact with and activate receptors on the surface of cells, and prominent among these is the receptor for advanced glycation endproducts (RAGE).
The goal of our research is to develop small drug-like molecules that will block the binding and activation of RAGE by AGEs, and thereby suppress the various disease manifestations caused by the over-abundance of AGEs in the blood stream.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
If our research is successful, we will have demonstrated a successful strategy and produced specific molecules that can prevent the interaction of AGEs with RAGE. These molecules will set the essential underpinning for determining RAGE if targeting activation of RAGE by AGEs is a viable drug development target for diabetes patients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
My father-in-law battled the adverse effects of diabetes for over 20 years and ultimately succumbed to the disease. He suffered most from progressive heart failure associated with atherosclerosis and related defects, which may well have arisen from the overabundance of AGEs in his blood and over-activation of RAGE and related receptors. My father is also afflicted with diabetes. These direct family ties bring the importance of diabetes research directly to my life on a daily basis, and that serves as motivation for me, as an accomplished biomedical researcher, to get involved.
This award will allow the development of a new line of diabetes research in our laboratory - the translation of our basic research program into the development of a drug to treat some of the devastating symptoms of the disease.
In what direction do you see the future of diabetes research going?
The future of diabetes research will develop in parallel in a range of different fundamentally important and complementary approaches. One major area will be understanding the intrinsic variation in our genes in normal individuals and the differences that arise in patients with the disease. A related development will follow the personalized medicine concept, where first a greater understanding of the variations of diabetes related genes will be generated and then treatments will be tailored for each patients in accord with this information.
A second area will be conversion of information about diabetes related genes into understanding at the molecular level how the actual proteins that they code for work and what exactly is wrong when they are defective. This degree of molecular understanding will provide the critical foundation for tailoring drugs to treat the specific ailments of diabetics with a minimal number of side effects.
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