Matrix metalloproteinases (MMPs) are a family of enzymes responsible for the proteolytic processing of extracellular matrix (ECM) structural proteins under physiological and pathological conditions. During sprouting angiogenesis, the MMPs expressed by a single endothelial "tip" cell exhibit proteolytic activity that allows the cells of the sprouting vessel to migrate into the ECM. Membrane type I matrix metalloproteinase (MT1-MMP) and the diffusible matrix metalloproteinase MMP2, and MMP9 in the presence of the tissue inhibitors of metalloproteinases TIMP1, TIMP2 and TIMP3, constitute a system of proteins that play an important role during the proteolysis of extracellular matrices. We have formulated biochemical models describing the activation and inhibition of the MMPs as well as the proteolysis of collagenous components. We have applied the biochemical model of MMP2, MT1-MMP and TIMP2 in a geometrically detailed model describing the migration of a single cell into a three dimensional collagen I matrix. An important proteolytic product of various ECM as well as circulating proteins are cryptic peptide fragments that modulate angiogenesis, they are inhibitors of angiogenesis. We introduced a systematic computational methodology based on bioinformatics that has enabled us to identify and classify over 120 novel endogenous peptide inhibitors of angiogenesis. The novel peptides are derived from members of the type IV collagen, thrombospondin, and CXC chemokine protein families, as well as coagulation factors, receptor tyrosine kinase-like orphan receptors, and various kringle-containing proteins. Their activity in suppressing the proliferation and migration of endothelial cells in vitro provided proof of principle for the validity of this computational method. Some of the novel peptides are derived from proteins known to be proangiogenic. By performing receptor neutralization studies, we have identified receptors to which these novel peptides bind. On the basis of this receptor binding information, we evaluated several examples of peptide-based combinatorial therapeutic strategies. In some cases, this combinatorial screening identified strong synergism. The peptides both as monotherapy and in combinations effectively arrest the tumor growth in a highly aggressive lung carcinoma xenograft model as well as inhibit neovascularization in corneal and choroidal angiogenesis models.
|Advisor:||Popel, Aleksander S.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 69/04, Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Bioinformatics|
|Keywords:||Angiogenesis, Antiangiogenic peptides, Extracellular matrix, Matrix metalloproteinases|
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