(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
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, In Press 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
Q. Zheng, J. Choi, L. Rouleau, R. L. Leask, J. A. Richardson, E. C. Davis and H. Yanagisawa, "Normal wound healing in mice deficient for fibulin-5, an elastin binding protein essential for dermal elastic fiber assembly" Journal of Investigative Dermatology, 126:2707-2714, August 2006
J. A. Spencer, S. L. Hacker, E. C. Davis, R. P. Mecham, R. H. Knutsen, D. Y. Li, R. D. Gerad, 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, February 2005
H. Yanagisawa, D. E. Clouthier, J. Charite, J. A. Richardson and E. N. Olson, "Targeted deletion of a brachial arch-specific enhancer reveals a role of dHAND in craniofacial development." Development, 130:1069-1078, 2003
SIGNIFICANT PUBLICATIONS
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
H. Yanagisawa, R. E. Hammer, J. A. Richardson, S. C. Williams, N. Emoto, S. Takeda and M. Yanagisawa, "Disruption of ECE-1 and ECE-2 reveals a role for endothelin converting enzyme-2 in murine cardiac development" Journal of Clinical Investigation, 105:1373-1382, 2000
H. Yanagisawa, M. Yanagisawa, R. P. Kapur, D. E. Clouthier, S. C. Williams, N. Emoto, J. A. Richardson and R. E. Hammer, "Dual genetic pathways of endothelin-mediated signaling defined by targeted disruption of endothelin converting enzyme-1 gene" Development, 125:825-836, 1998
H. Yanagisawa, R. E. Hammer, J. A. Richardson, S. C. Williams, D. E. Clouthier and M. Yanagisawa, "Role of endothelin-1/ endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice." J. Clin. Invst., 102:22-33, 1998
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