Stroke and vascular dementia are prevalent diseases which are both caused by multiple factors, including genetic susceptibility. In large part, the genetics of these disorders is complex. However, in families with CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), premature stroke and vascular dementia are caused by defects in the Notch3 gene. Our broad goal is to identify the molecular pathways governing the pathogenesis of CADASIL, which will help shed light on more common forms of stroke and dementia. The central hypothesis is that mutant NotchS, expressed in arterial smooth muscle, triggers a series of cellular changes that result in inhibition of the proteasome. The proteasome is essential for the degradation of proteins via the ubiquitin proteasome system and has been implicated in several neurodegenerative disorders. We propose that inhibition of the proteasome in vascular smooth muscle causes cell toxicity and is linked to the breakdown of cell-cell contacts and accumulation of Notch3 protein, two pathological features of CADASIL. In support of this concept, we present preliminary data showing that Notch3 specifically interacts with a subunit of the 26S proteasome. In addition, we demonstrate evidence that proteasome inhibition is increased in cells expressing mutant Notch3. Finally, proteasome inhibition in cultured smooth muscle cells causes cell-cell separation and cell death, two features seen in CADASIL tissues.
In Specific Aim 1, we will characterize whether mutant Notch3 directly inhibits proteasomes and whether mutant Notch3 over-expression leads to proteasome inhibition in cell culture and in arteries of transgenic animals.
In Aim 2, we will determine whether proteasome inhibition leads to cell-cell contact disruption and Notch3 protein accumulation in culture and in vivo. Finally, in Aim 3, we will investigate whether cell death due to proteasome inhibition is exacerbated by Notch3 mutations and by cell-cell contact disruption. These experiments will support a CADASIL pathway involving proteasomal inhibition and may have implications for the pathogenesis of other vascular and proteasome-linked diseases. In lay language, this application is designed to investigate the molecules involved in a disease, CADASIL that causes stroke and dementia. An understanding of CADASIL may provide clues to designing better treatments and prevention strategies for stroke and dementia. What is learned from this study may also provide information that will be useful for the treatment of other vascular diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02NS054724-01
Application #
7078341
Study Section
NST-2 Subcommittee (NST)
Program Officer
Refolo, Lorenzo
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$172,140
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Xiaojie; Lee, Soo Jung; Young, Marian F et al. (2015) The small leucine-rich proteoglycan BGN accumulates in CADASIL and binds to NOTCH3. Transl Stroke Res 6:148-55
Zhang, Xiaojie; Lee, Soo Jung; Young, Kelly Z et al. (2014) Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state. Brain Res 1583:230-6
Lee, Soo Jung; Zhang, Xiaojie; Wang, Michael M (2014) Vascular accumulation of the small leucine-rich proteoglycan decorin in CADASIL. Neuroreport 25:1059-63
Zhang, Xiaojie; Meng, He; Wang, Michael M (2013) Collagen represses canonical Notch signaling and binds to Notch ectodomain. Int J Biochem Cell Biol 45:1274-80
Meng, He; Zhang, Xiaojie; Lee, Soo Jung et al. (2013) Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling. PLoS One 8:e75808
Wang, Michael M; Xi, Guohua; Keep, Richard F (2013) Should the STAIR criteria be modified for preconditioning studies? Transl Stroke Res 4:3-14
Dong, Hairong; Ding, Haixia; Young, Kelly et al. (2013) Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL. Stroke 44:1456-8
Wang, Michael M; Lee, Soo Jung; Kim, Jisu et al. (2013) ABO blood antigens define human cerebral endothelial diversity. Neuroreport 24:79-83
Frieler, Ryan A; Ray, Jessica J; Meng, He et al. (2012) Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex. J Am Heart Assoc 1:e002584
Dong, Hairong; Blaivas, Mila; Wang, Michael M (2012) Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Res 1456:64-71

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