(1) Cell-ECM (extracellular matrix) crosstalk Microenvironment of the vascular wall is provided by various ECM proteins and growth factors and plays a critical role in normal development and diseases. The concept of ECM as a structural protein has been challenged with a new view that it can modulate cell proliferation and migration by directly activating intracellular signaling pathways via surface receptor(s), indirectly sequestering growth factors in the extracellular space, and by modifying the microenvironment through interacting with various secreted proteases and enzymes. We utilize a mouse system to examine a loss or gain of function of ECM proteins on normal vascular development. Specifically, we are interested in the role of ECM in establishment of the vascular wall integrity and regulation of angiogenesis and arteriogenesis. We also study how ECM affects tumor development and progression of vascular diseases, such as injury-induced neointima formation and atherosclerosis. We currently focus on fibulin family ECM proteins, which is consisted of six known members and characterized by tandem repeats of calcium-binding EGF motifs. We take biochemical and molecular biological approaches to search for novel fibulin interacting proteins, and generate various knockout mice to investigate their in vivo functions.
(2) Molecular mechanism of neural crest (NC) development NC cells originate from the dorsal lip of the neural tube and migrate to the branchial arches. NC cells receive inductive signals from the overlying epithelium and surrounding mesenchyme and initiate developmental programs. The long-term goal of my research is to understand the inter-and intra-signaling pathways involved in development of cranial and cardiac NC cells. We study the basic helix-loop-helix transcription factors Hand1 and Hand2, which are expressed in the distal mesenchyme of branchial arches and regulated by the upstream endothelin signaling. We are trying to identify Hand interacting proteins as well as downstream target genes to establish the transcriptional circuitry during NC development.
RESEARCH INTERESTS
Molecular mechanism of vascular development
Regulation and signaling during cardiovascular remodeling
Elastic fiber formation in vivo
Developmental program of neural crest-derived tissues
ECM and tumor angiogenesis
RECENT PUBLICATIONS
M. K. Schluterman, S. L. Chapman, G. Korpanty, K. Ozumi, T. Fukai, H. Yanagisawa, R. A. Brekken, "Loss of Fibulin-5 binding to beta1integrins inhibits tumor growth by increasing the level of ROS" Diseases Models & Mechanisms, In press 2010
S. L. Chapman, F.-X. Sicot, E. C. Davis, J. Huang, T. Sasaki, M.-L. Chu, H. Yanagisawa, "Fibulin-2 and Fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury" Arterioscler Thromb Vasc Biol, E-Pub. 2009
N. Funato, S. L. Chapman, M. D. McKee, H. Funato, J. A. Morris, J. M. Shelton, J. A. Richardson, H. Yanagisawa, "Hand proteins control osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2" Development, 136:615-625, 2009
A. C. Barbosa, N. Funato, S. L. Chapman, M. D. McKee, J. A. Richardson, E. N. Olson and H. Yanagisawa, "Hand transcription factors cooperatively regulate development of the distal midline mesenchyme" Developmental Biology, 310:154-168, 2007
Q. Zheng, E. C. Davis, J. A. Richardson, B. C. Starcher, T. Li, R. D. Gerard, and H. Yanagisawa, "Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers" Molecular and Cellular Biology, 27:1083-1095, February 2007
SIGNIFICANT PUBLICATIONS
Q. Zheng, J. Choi, L. Rouleau, R. L. Leask, J. A. Richardson, E. C. Davis, H. Yanagisawa, "Normal Wound healing in mice deficient for fibulin-5, an elastin binding protein essential for dermal elastic fiber assembly" J. Invest. Derm., 126:2707-2714, 2006
J. A. Spencer, S. L. Hacker, E. C. Davis, R. P. Mecham, R. H. Knutsen, D. Y. Li, R. D. Gerard, J. A. Richardson, E. N. Olson, H. Yanagisawa, "Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration" Proc. Natl. Acad. Sci., 102:2946-2951, 2005
H. Yanagisawa, E. C. Davis, B. C. Starcher, T. Ouchi, M. Yanagisawa, J. A. Richardson, and E. N. Olson, "Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo" Nature, 415:168-171, January 2002
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