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Sakai
Lab
 Research interest:
Mutations in fibrillin-1 lead
to the autosomal dominant disorder Marfan syndrome, which manifests
in many clinical symptoms which develop primarily in the
cardiovascular, skeletal, and ocular systems including mitral valve
disease, progressive dilation of the aortic root, dolichostenomelia,
arachnodactyly, scoliosis, and ectopia lentis. Dissection and
rupture of the aortic wall is the major life‐threatening
clinical complication. Impaired tissue integrity was originally
thought to be the major cause for Marfan syndrome, but more recently
mouse models of Marfan syndrome have revealed that fibrillin-1
mutations also perturb local TGF-β
signaling.
The working hypothesis
of the Sakai laboratory is that fibrillin containing microfibrils,
which are ubiquitous throughout the connective tissue space,
function as information highways along which growth factor signals
are embedded. By binding to latent growth factor complexes,
fibrillins can target signals to specific sites in the extracellular
matrix. Extracellular microfibrils can thus serve as tissue-specific
and temporally regulated structural scaffolds to spatially
concentrate and direct presentation of growth factors.
I am interested in understanding how the fibrillin containing
microfibril scaffold can regulate growth factor activity. In a first
effort we were able to show that growth factors belonging to the TGFβ
superfamily-- typically forming latent
complexes with their propeptides-- are interacting via their
propeptides with fibrillin-1, and -2 in vitro.
Immunofluorescence of mouse tissues could confirm this finding by
detecting fibrillar staining for growth factors suggesting a new
mechanism by which these cytokines might be sequestered and stored
by the microfibril network.
Ongoing studies of fibrillin mutant mice indicate that BMP growth
factor staining is perturbed. These studies may provide in vivo
evidence for an essential role performed by fibrillin in the
extracellular regulation of BMP signaling. Future studies should be
directed toward the integration of these complex signaling pathways
by the extracellular physical scaffold and toward the roles
performed by cells as they interact coordinately with stored growth
factors and with the scaffold.
BIOGRAPHICAL SKETCH
Name:
Gerhard Sengle
Title:
Mentored
Scientist
Role on Project:
Postdoctoral Fellow
Honors:
2003 DFG Research
Stipend
Institution
& Location
Degree
Year(s) Field of
Study
University of Munich, Germany
M.S. 1998
Chemistry/Biochemistry
University of Bonn, Germany
Ph.D. 2001
Biochemistry
Research and/or Professional
Experience:
2003 – present Shriners
Hospital for Children Research, Portland Unit, Portland, OR:
Mentored Scientist
2001-2003 Center for Biochemistry, University of Cologne,
Germany: post-doctoral research with
Mats Paulsson and Raimund Wagener; Investigating the function of the
Matrilins, a recently discovered family of non-collagenous
extracellular matrix proteins.
1998-2001 Laboratory for Molecular Biology (Gene Center) in Munich,
and the Kekulé-Institute for Organic Chemistry and Biochemistry in
Bonn: Ph.D. thesis with Michael
Famulok In vitro selection and
engineering of novel ribozymes, RNA biopolymers capable of
accelerating organic chemical reactions.
1997-1998 Laboratory for Molecular Biology (Gene Center) in Munich,
and the Institute of Chemistry, Division Biochemistry, Free
University of Berlin, Diploma-Thesis with Michael Famulok and Andres
Jäschke. Developing of strategies for introducing chemical
derivatisations at RNA 5’-ends.
Peer-Reviewed Publications (published, in press and
submitted):
Sengle, G.,
Jenne, A., Arora, P.S., Seelig, B., Nowick, J.S., Jaschke, A., and
Famulok, M. Synthesis, incorporation efficiency, and stability of
disulfide bridged functional groups at RNA 5'-ends. Bioorg Med
Chem, 8, 1317-29, 2000.
Sengle, G., Eisenfuhr, A., Arora, P.S., Nowick, J.S., and
Famulok, M. Novel RNA catalysts for the Michael reaction. Chem
Biol, 8, 459-73, 2001.
Eisenfuhr, A., Arora, P.S., Sengle, G., Takaoka, L.R., Nowick,
J.S., and Famulok, M. A ribozyme with michaelase activity: synthesis
of the substrate precursors. Bioorg Med Chem, 11, 235-49,
2003.
Sengle, G.,
Kobbe, B., Morgelin, M., Paulsson, M., and Wagener, R.
Identification and characterization of AMACO, a new member of the
von Willebrand factor A-like domain protein superfamily with a
regulated expression in the kidney. J Biol Chem 278,50240-9,
2003.
Wagener, R., Ehlen, H.W., Ko, Y.P., Kobbe, B., Mann H.H., Sengle
G., Paulsson M. The matrilins--adaptor proteins in the
extracellular matrix. FEBS Lett 579,3323-9, 2005 (Review).
Mann, H.H.*, Sengle, G.*, Gebauer, J.M., Eble, J.A., Paulsson,
M., Wagener, R. Matrilins mediate weak cell attachment without
promoting focal adhesion formation. Matrix Biol 26,167-74,
2007 (*: equal first authors).
Kuo, C.L., Isogai, Z., Keene, D.R., Hazaki, N., Ono, R.N., Sengle,
G., Bächinger, H.P., Sakai, L.Y., Effects of fibrillin-1
degradation on microfibril ultrastructure. J Biol Chem
282,4007-20, 2007.
Sengle, G.,
Charbonneau, N.L., Ono, R.N., Sasaki, T., Alvarez, J., Keene, D.R.,
Bachinger. H.P., Sakai, L.Y. Targeting of bone morphogenetic protein
growth factor complexes to fibrillin. J
Biol Chem.
283,13874-88, 2008.
Sengle, G., Ono, R.N., Lyons, K.M., Bächinger, H.P., Sakai,
L.Y. A New Model for Growth Factor Activation: Type II Receptors
Compete with the Prodomain for BMP-7. J Mol Biol 381,
1025-39, 2008.
Sengle, G., Charbonneau, N.L., Ono, R.N., Sakai, L.Y.
Connective tissue pathways that regulate growth factors. Primer on
the Metabolic Bone Diseases and Disorders of Mineral Metabolism,
7:27-32, 2008 (book chapter).
Ono, R.N., Sengle, G., Charbonneau,
N.L., Carlberg, V., Bächinger, H.P., Sasaki, T., Lee-Arteaga, S.,
Zilberberg, L., Rifkin, D.B., Ramirez, F., Chu, M.L., Sakai, L.Y.,
Latent Transforming Growth Factor {beta}-binding Proteins and
Fibulins Compete for Fibrillin-1 and exhibit Exquisite Specificities
in Binding Sites. J Biol Chem 284:16872-81, 2009.
Ehlen, H.W., Sengle, G., Klatt, A.R.,
Talke, A., Müller, S., Paulsson, M., Wagener, R., Proteolytic
processing causes extensive heterogeneity of tissue matrilin forms.
J Biol Chem. 2009 Jun 16 [Epub ahead of print]
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