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On the genetics of intracranial aneurysm and on growth factor induced angiogenesis in the murine brain

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Title: On the genetics of intracranial aneurysm and on growth factor induced angiogenesis in the murine brain
Author: Gaal, Emilia
Contributor: University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, NeurosurgeryThe Neurosurgery Research Group, National Institute for Health and Welfare; Institute for Molecular Medicine Finland, Molecular/Cancer Biology Laboratory, Haartman Institute and Biomedicum Helsinki, Faculty of Medicine, University of Helsinki, Finland; The Yale Neurogenetics Program, Yale School of Medicine, New Haven, CT, USA
Thesis level: Doctoral dissertation (article-based)
Abstract: Cerebrovascular diseases continue to challenge us by robbing lives and leaving many disabled still in their prime working age. Some cerebrovascular diseases are more acute in nature, and some erode the quality of life over a long period of time.

A life-threatening form of acute cerebrovascular disease is brought on by the rupture of an intracranial aneurysm (IA). Most IAs are berry-shaped pouches at the forking site of cerebral arteries. Since according to autopsy results, 2-5% of the population harbours IA, it is a common disease. Most IA go unnoticed during one s lifetime, however, often the first symptom they give is their deadly rupture. Likely, both environmental factors and a compound genetic susceptibility, contribute to the risk of IA, making it a complex disease. The aim of studies I-III was to test whether in humans common genetic variants contribute to the susceptibility to IA (I,II), and to seek genetic evidence for their pathomechanism (III). In multinational genome-wide association studies (I,II) we identified 5 loci with strong statistical evidence of association with IA, and a further 14 loci with suggestive evidence. Further, we found that suggestive IA risk locus at 5q26 is strongly associated with high systolic blood pressure in over 210 000 individuals of European descent, highlighting the connection between hypertension and IA (III).

To gain further insight into cerebral vasculopathies and to facilitate the development of novel therapies, in study (IV) we turned our attention to vascular growth factor induced angiogenesis in a model organism. We tested by viral gene transfer the known vascular growth factors in the murine central nervous system and characterised extensively the angiogenesis upon treatment. The aim of the study was to identify the best candidate vascular growth factor(s) for therapeutic brain angiogenesis. We identified placenta growth factor as the most safe and efficient candidate for therapeutic revascularisation of the central nervous system. We envision a placenta growth factor enhanced multiple bur hole indirect extracranial-intracranial bypass as a novel therapeutic approach in the brain, possibly aiding the treatment of diseases such as chronic cerebral hypoperfusion, complex IAs and stroke.Cerebrovascular diseases continue to challenge us by robbing lives and leaving many disabled still in their prime working age. Some cerebrovascular diseases are more acute in nature, and some erode the quality of life over a long period of time.

A life-threatening form of acute cerebrovascular disease is brought on by the rupture of an intracranial aneurysm (IA). Most IAs are berry-shaped pouches at the forking site of cerebral arteries. Since according to autopsy results, 2-5% of the population harbours IA, it is a common disease. Most IA go unnoticed during one s lifetime, however, often the first symptom they give is their deadly rupture. Likely, both environmental factors and a compound genetic susceptibility, contribute to the risk of IA, making it a complex disease. The aim of studies I-III was to test whether in humans common genetic variants contribute to the susceptibility to IA (I,II), and to seek genetic evidence for their pathomechanism (III). In multinational genome-wide association studies (I,II) we identified 5 loci with strong statistical evidence of association with IA, and a further 14 loci with suggestive evidence. Further, we found that suggestive IA risk locus at 5q26 is strongly associated with high systolic blood pressure in over 210 000 individuals of European descent, highlighting the connection between hypertension and IA (III).

To gain further insight into cerebral vasculopathies and to facilitate the development of novel therapies, in study (IV) we turned our attention to vascular growth factor induced angiogenesis in a model organism. We tested by viral gene transfer the known vascular growth factors in the murine central nervous system and characterised extensively the angiogenesis upon treatment. The aim of the study was to identify the best candidate vascular growth factor(s) for therapeutic brain angiogenesis. We identified placenta growth factor as the most safe and efficient candidate for therapeutic revascularisation of the central nervous system. We envision a placenta growth factor enhanced multiple bur hole indirect extracranial-intracranial bypass as a novel therapeutic approach in the brain, possibly aiding the treatment of diseases such as chronic cerebral hypoperfusion, complex IAs and stroke.
URI: URN:ISBN:978-952-10-8369-3
http://hdl.handle.net/10138/37553
Date: 2012-11-30
Copyright information: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
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