Dissertation
Evaluation of Angiotensin IV Analogue Effects Mediated by the Hepatocyte Growth Factor and c-Met System
Doctor of Philosophy (PhD), Washington State University
01/2011
Handle:
https://hdl.handle.net/2376/117146
Abstract
Angiotensin IV (VYIHPF) is a peptide that binds to the AT4 receptor in the brain and periphery to mediate its actions which include: depression, regulation of cerebral blood flow, cerebroprotection and regulation of fluid homeostasis, hormonal balance and hypertension. Most notably angiotensin IV and the AT4 receptor have been implicated in cognitive processes. This has been demonstrated by their ability to overcome chemically and physically induced learning and memory impairments such as scopolamine induced amnesia, perforant path cuts to the hippocampus and kainic acid injections in the CA1 region of the hippocampus. Native angiotensin IV has a half-life of only seconds in the blood before being degraded by proteolytic enzymes. Thus more stable angiotensin IV analogues have been synthesized to study their function in the brain and to create peptidomimetics targeting neurodegenerative diseases and dementias such as those imposed by Alzheimer's disease, aging and stroke. Many of these analogues however are also easily degraded by aminopeptidases while their large size and hydrophilic nature prevent them from crossing the blood brain barrier, a necessity for a CNS pharmaceutical. Despite promising pro-cognitive activities that have been observed in vivo, there is a lack of understanding of the mechanism involved. This dissertation presents results providing insights into the mechanism involved in the pro-cognitive effects of these angiotensin IV analogues. In addition, the development of a biologically stable and orally active angiotensin IV analogue is described and the identity of the AT4 receptor is confirmed. Since the discovery of the AT4 receptor by our laboratory in 1992, its identity has eluded us however; evidence published by our laboratory indicates that the true receptor is c-Met and its ligand, Hepatocyte Growth Factor.
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Details
- Title
- Evaluation of Angiotensin IV Analogue Effects Mediated by the Hepatocyte Growth Factor and c-Met System
- Creators
- Caroline Clare Benoist
- Contributors
- Joseph W Harding (Advisor)Gary A Wayman (Advisor)John W Wright (Committee Member)Michael Varnum (Committee Member)Peter C Meighan (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 151
- Identifiers
- 99900581548601842
- Language
- English
- Resource Type
- Dissertation