The objective of this grant proposal is to teach research skills which will enhance the candidate's ability to investigate fundamental questions concerning the interaction of lymphocytes and macrophages with the vessel wall, which may lead to the development of atherosclerosis (ATS). A rat model of atherosclerosis, developed by the sponsor's laboratory will be examined and compared to the lesions observed in human arteries. Specifically, the following research aims will be addressed: (a) THE STICKING OF CELLS TO THE VASCULAR WALL, a main characteristic of inflammation, is also characteristic of early ATS. Could it be that the major risk factors of ATS (hypertension, smoking, diabetes) operate by enhancing the cellular sticking? (b) THE REGRESSION of atherosclerosis is now known to be a possibility. Does it correspond to a decrease in the """"""""cellular sticking"""""""" just described? (c) WHAT TYPES OF WHITE BLOOD CELLS ARE INVOLVED IN ATHEROSCLEROSIS. The sponsor's laboratory found that a significant proportion of the cells involved (in human and animal ATS) are LYMPHOCYTES, which may play a key role in the development of the lesions. (d) Past studies on experimental ATS have found that three sets of events can occur: CELL STICKING, INCREASED PERMEABILITY (also typical of inflammation) and DEPOSITION OF FAT. How do these three events correlate in time and in space? Which one comes first? Does any one bring about the other two? (e) HOW DOES ATS RELATE TO """"""""ALLERGY""""""""? It has long been thought that there may be a relationship between the two. (f) WHAT KIND OF CELLULAR RESPONSES ARE INDUCED BY CHOLESTEROL COMPOUNDS, if they are introduced under the skin? The answers may well help to understand some of the arterial changes induced by these compounds. The techniques to be learned will include lipoprotein electrophoresis, morphometry, radioautography, immunocytochemistry and immunoelectron microscopy, en face tissue analysis, experimental surgery, and the biotechnology of the slow release pellet. Ultimately, during the fourth and fifth years, an independent research project will be developed which will integrate the laboratory skills mastered in the first three years and apply them to an independent project which will further define and utilize animal models to understand fundamental questions concerning atherosclerosis, a devastating human health problem.
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