The objective of this project is to determine the cellular/molecular connection between advanced glycation end products and its receptors which can be found on monocytes and macrophages. This interaction and its involvement in collateral circulation is relevant to the health of the millions of diabetic patients in the world. The cellular changes that occur in hyperglycemic patients have proven to decrease the development of collateral circulation leading to decreased blood flow in areas of ischemia. The purpose of this study is to compare collateral vessel development in animals based on their expression of RAGE in monocytes/macrophages, specifically. Research Design: To compare collateral vessel development in animals with normal bone marrow and those that overexpress RAGE through a specific technique by which human RAGE retrovirus that specifically overexpresses RAGE in monocytes/macrophages is transplanted into bone marrow after irradiation. Four treatment groups will be used (femoral artery ligation and excision in normals and and diabetics and sham operation in normals and diabetics). These subjects will be divided into controls, BMT with untreated bone marrow, BMT with GFP transduced retrovirus, and BMT with hRAGE transduced retrovirus. Approximately, 10-14 subjects will be needed for each combination of subject and treatment group. Micro-CT as well as Laser Doppler Perfusion Imaging will be used to determine the primary endpoint of vascular volume. Also, in question is the effect of having RAGE null mice. Therefore, the same treatment groups will be used with subjects now consisting of a control, RAGE null mice without BMT, RAGE positive mice with BMT from RAGE positive mice, RAGE positive mice with BMT from RAGE null mice, RAGE null mice with BMT from RAGE null mice, RAGE null mice with BMT from RAGE positive mice. Through this method, a complementary study to the former can be conducted which shows the effect of decreased RAGE expression on collateral growth.
Millions of people worldwide are affected by the morbid side effects of poorly controlled diabetes and these numbers are expected to increase dramatically in the next few decades. By obtaining a better understanding of how hyperglycemia alters the normal processes of the human body, we can decrease the morbidity and mortality associated with this disease through medications that can prevent these processes from occurring.
