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MASSACHUSETTS
Cell Biology, Harvard Medical School -
click on this link to find out what this lab accomplishing with CADASIL.
http://artavanis-tsakonas.med.harvard.edu/SATResearch.html
understanding the molecular nature of the mutations associated with the CADASIL
I
am very impressed to see the progress you have made in promoting awareness of CADASIL
using the Foundation’s website. I also appreciate you posted information about our
laboratory (Dr. Artavanis-Tsakonas laboratory at Harvard University) in the research
section of your website. The purpose of this message is to update you on the progress we
have made in our research. During the past few months we have made very important advances
towards the development of animal models of CADASIL using both flies and mice. As you
know, animal models of human disorders are an extremely important tool to better
understand the pathological mechanisms of disease. Moreover, animal models are also
essential to determine the safety and effectiveness of drugs. Specifically, we have
generated mice carrying either a normal human Notch3 gene or two different Notch3 genes
carrying specific CADASIL mutations. In addition, we are currently performing pathological
and biochemical analyses of human brain samples from deceased CADASIL patients. The goal
of these studies is to determine the composition of the granular osmiophilic deposits
(GOM) that accumulate in the arteries of patients suffering CADASIL. As you know the
characterization of brain deposits in other diseases such as Alzheimer’s and
Parkinson’s has provide crucial insights into the pathophysiological mechanisms of
these disorders. In a similar way, the characterization of the GOMs may provide us with
clues regarding the mechanism through which Notch3 mutations lead to CADASIL. I want to
reassure you our team of scientist is doing everything in their hands to better understand
how CADASIL works and how to treat this devastating disorder. Sincerely yours, Joseph F.
Arboleda-Velasquez, M.D. dated 2-5-06
For
charitable donations to the CADASIL research project Dr. Spyros Artavanis-Tsakonas
laboratory, checks should be made out to: The General Hospital Corp. (d.b.a Massachusetts
General Hospital) and sent to: Massachusetts General Hospital. Development Office. 100
CRP, Suite 600. Boston, MA 02114. Phone: (617) 726-0402. Fax: (617) 726-7661. Attn: Kate
Todd
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MICHIGAN
Michael Wang MD PhD
http://sitemaker.umich.edu/wang.lab/cadasil
A
Mouse Model -
CADASIL
(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy) causes recurrent strokes and vascular dementia. The disease is caused
most commonly by a single point mutation in the Notch3
gene, which leads to alteration in the number of cysteines. Abnormality in cysteine
number may cause misfolding of the protein, leading to arterial smooth muscle dysfunction.
The lab is currently studying the mechanism of how mutant Notch3 leads to cellular injury.
We are attempting to identify protein partners of Notch3.
We are also actively pursuing the mechanisms of how the Notch3 gene is regulated, which
may lead to ways to control Notch3 protein levels, which are typically elevated in CADASIL
patients.
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THE
CADASIL PROJECT - No longer exists
Dr. Schanen
http://www.genetics.ucla.edu/labs/schanen/cadasil.html
Structure of the Notch 3 Protein
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FRANCE
www.Cadasil.com
In France, a study was realized by the team of neurologie of the hospital Lariboisière
(to Paris) concerning the aspects of the disease in Imagery by Magnetic Resonance. This
study allowed specifying the apparition age and the evolution of the wronged white
cerebral substance. A second phase of the study has for objective to evaluate in a manner
individual the observed modifications in imagery during the time with the patients from
examinations IRM repeated.
A
project of followed common of 200 patients is currently in course (beginnings in 2003 and
2004, for a period of 3 years). The body of the patients is
subjected to the same protocol of examinations and to a followed half-yearly, centralized
to the hospital Lariboisière. Financings are
essential to accomplish these researches. Several associations as the Foundation
for the Medical Research or France Alzheimer, and certain laboratories as Servier, Rhône
Poulenc, Merieux contributed to the financing of the already realized studies.
The
hope of a preventive treatment rests on the pursuit and the development of research works
in the domain clinic (therapeutic essays, follow by the patients) and basic (genetic,
biological).
The website is cadasil.com, please remember to use the http://www.freetranslation.com
translator to read the website as it is in French.
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WEST
GERMANY
Genetics of Stroke – CADASIL
http://www.neurogenetik.de/neuro/Projekte/Stroke/body_stroke.html
Cerebral
autosomal dominant arteriopathy with subcortical strokes and leukoencephalopathy (CADASIL)
is the most important monogenic cause of stroke and vascular dementia (more than 200
families in Germany). Our group has been involved in the initial characterization of the
disease (clinical, MRI, and genetic aspects of the disease) and an increasing number of
families are followed at our Neurogenetic outpatient clinic.
We
offer genetic testing for NOTCH3
mutations and examination of blood vessels from skin biopsies to check for CADASIL-typical
ultrastructural deposits. Mutations in the NOTCH3
gene are being identified by a direct sequencing approach for exons 3 and 4 and by DHPLC
for the remaining exons.
Ongoing
research projects include:
Cell
culture and biochemical studies on the molecular and cellular biology of wild type and
mutant variants of the Notch3 receptor (DFG funded project within the SFB 596).
Generation of a transgenic mouse model for CADASIL (DFG funded project within SFB 596).
Studies on brain perfusion including interventional studies (Pfizer grant).
Neuroimaging studies evaluating the relationship between brain perfusion, structural
changes, and functional alterations using various neuroimaging techniques (MRI, PET,
Doppler sonography) clinical tests (DFG funded project).
A large study to identify quantitative trait loci for ischemic lesions (DFG funded
project)
There is an ongoing study on the impact of vascular lesions on cognition (‘vascular
dementia’).
Genetic
risk factors for stroke
Another area of research is the identification of genetic risk factors for stroke. A large
data-basis (DNA and clinical information) from patients with stroke has been established.
Studies are pursued in collaboration with other clinical centres and a high-throughput
facility.
The
most direct way of looking at our research acitivities is to look at our publications
which can be accessed through the scientific databases
(eg.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed).
In
addition, we have our own web page which however is mostly in German (www.neurogenetik.de),
remember to use the http://www.freetranslation.com to translate.
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SCOTLAND
Dr K W Muir
Southern
General Hospital
Telephone:
0141 201 2502
Ambulatory
blood pressure monitoring in (CADASIL).- is
blood pressure in cadasil patients abnormal when compared to controls? Do they have a
normal nocturnal dip? Is there a correlation between phonotype and blood pressure?
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ENGLAND
London
St
Georges Hospital NHS Trust - lead centre
Collection
of DNA resource for small vessel disease (stroke) - part of collection will be screening
for cadasil
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NETHERLANDS
Diagnostic
Notch3 [?] sequence
analysis in CADASIL:
three new mutations in Dutch patients. Dutch CADASIL
Research Group.
Oberstein SA, Ferrari MD, Bakker E, van Gestel J, Kneppers AL, Frants RR, Breuning MH, Haan J
Department of Clinical Genetics, Leiden University Medical Center, The Netherlands.
To confirm the clinical diagnosis in individual Dutch patients with cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL),
we performed direct sequence
analysis of the abnormal gene, Notch3 [?], in patients from 11
families without prior linkage analysis to chromosome
19. Eleven missense
mutations involving the loss or gain of a cysteine
residue were found, of which 3 are new. Exon
4 is a mutation hotspot (9 of 11 families). Notch3 [?] sequence
analysis of CADASIL
patients in a diagnostic laboratory is a feasible procedure to confirm the clinical
diagnosis in individual patients.
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Revised: April 11, 2008
CADASIL Together We Have Hope Non Profit Organization
3605 Monument Drive
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info@cadasilfoundation.org
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