Genetics and Pathobiology of Vascular Cognitive Impairment (R01)
Department of Health and Human Services
National Institutes of Health (NIH), (http://www.nih.gov)
Purpose – The National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Aging (NIA), and the National Heart, Lung and Blood Institute (NHLBI) invite research grant applications aimed at understanding the genetics and pathobiology of Vascular Cognitive Impairment (VCI).
Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well studied than that of AD. This lack has been due in part to the clinical heterogeneity of the disease, and also to poor understanding of its pathology at the cellular level. Recently, however, research in VCI has taken some critical first steps forward. A genetic form of vascular dementia, CADASIL, has been discovered, and the mutant gene identified as Notch 3. Previous research in animal models had shown Notch 3 to be important in early neural and vascular development. The finding that mutation of Notch 3 leads to stroke and dementia (both seen in CADASIL) suggests that the gene also plays an important role in the function or maintenance of vascular and/or neural cells in the adult. Consistent with this possibility, a transgenic mouse carrying the mutant form of Notch 3 has now been generated which shows degeneration of smooth muscle cells similar to that seen in human patients. These findings provide an important foothold for understanding the cell biology as well as the genetics of VCI. Moreover, the known interaction of Notch with the presenilin proteins suggests a juncture in the disease pathways underlying VCI and AD, which also could be further explored in mouse models.