Brain specific non-AT1, non-AT2 angiotensin binding site

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DESCRIPTION (provided by applicant): There are many uncertainties about the brain angiotensin system and its functionality is controversial. However, it is generally accepted that brain angiotensin causes hypertension and other cardiovascular disorders. With the recognition of functionality of peptide fragments of angiotensin II some having their own receptors, it is now known that brain angiotensins have a multitude of functions extending well beyond regulation of the cardiovascular system. We recently discovered a non-AT1, non-AT2 binding site in the brain that may add an additional layer of complexity to the brain angiotensin system. It is present in higher quantities than either of the major angiotensin receptor subtypes and could function either as a novel receptor for angiotensins that may be limited to the brain, or it could be a highly specific angiotensinase that plays a critical role in the metabolism of angiotensin peptides. To better understand this binding site, this project is directed to further characterizing this novel, brain-specific non-AT1, non-AT2 binding site for angiotensin peptides. The first specific aim is to define its biochemical characteristics through polyacrylamide gel purification and sequencing techniques to determine the amino acid sequence and structure of the binding site. The second specific aim is to determine its pharmacological specificity to determine if this binding site is specific for angiotensin peptides or if it has a broader substrate/ligand specificity. The third specific aim will study the distribution of the binding site in the brain and ascertain whether conditions associated with altered brain angiotensin system regulation of the cardiovascular system or pathophysiological conditions, e.g., brain ischemia as in stroke, genetic or experimental hypertension and in transgenic mice lacking angiotensin receptors, can alter the expression of this binding site in specific brain regions. The changes should enable us to do a functional neuroanatomical assessment of its possible participation in physiological and pathophysiological circumstances. It is anticipated that this protein will prove to be of considerable importance in the functionality of the brain angiotensin system. Since the brain angiotensin system is notorious for causing cardiovascular disease, this research could lead to the development of novel therapeutic strategies for treatment of hypertension and stroke. However the occurrence of this binding site in high concentrations in brain regions such as the nucleus basalis of Meynert, substantia nigra, amygdala, nucleus accumbens and substantia gelatinosa of the spinal cord could explain the proposed involvement of the brain angiotensins system in Alzheimer's and Parkinson's Disease, stress and anxiety disorders, drug abuse and chronic pain. PUBLIC HEALTH RELEVANCE: Cardiovascular disease, especially hypertension, is the leading cause of death (629,000 in 2006) in the US. In addition to causing heart failure and kidney damage, hypertension is the primary cause of strokes, which killed 137,000 Americans in 2006, and leaves many others with severe motor and cognitive impairments. The hormone most commonly associated with cardiovascular morbidity is angiotensin II (Ang II). It is arguably the most potent blood pressure-raising hormone. But in addition, it has pathophysiological effects separate from its ability to cause high blood pressure. It is now known that Ang II is made in the brain and exerts powerful influences on the brain systems that regulate blood pressure. Perhaps half of Ang II's ability to raise blood pressure may occur via its actions in the brain. At least one drug company is investigating drugs that specifically target the brain angiotensin system as a treatment for high blood pressure. However, we still do not know how the brain angiotensin system works. We recently discovered a novel binding site for Ang II that is highly expressed and widely distributed throughout the brain in several species including humans. This proposal aims to determine the structural identity and functionality of this novel angiotensin binding site in the brain to assess its role in mediating or antagonizing the pathophysiological actions of Ang II in the brain.