Modified VEGF-A with improved angiogenic properties

The present invention is directed to methods and compositions for making and using chimeric polypeptides that comprise a VEGFR-2 ligand. The chimeric molecules of the present invention retain VEGFR-2 binding activity and an enhanced angiogenic activity as compared to native VEGF-A

Evolution of the vertebrate parahox clusters

The ParaHox cluster contains three Hox‐related homeobox genes. The evolution of this sister of the Hox‐gene clusters has been studied extensively in metazoans with a focus on its early evolution. Its fate within the vertebrate lineage, and in particular following the teleost‐specific genome duplication, however, has not received much attention. Three of the four human ParaHox loci are linked with PDGFR family tyrosine kinases. We demonstrate that these loci arose as duplications in an ancestral vertebrate and trace the subsequent history of gene losses. Surprisingly, teleost fishes have not expanded their ParaHox repertoire following the teleost‐specific genome duplication, while duplicates of the associated tyrosine kinases have survived, supporting the hypothesis of a large‐scale duplication followed by extensive gene loss

Virtual Skrining Senyawa Turunan Flavonoid dari Genus Artocarpus sebagai Inhibitor VEGFR-2

Vascular Endothelial Growth Factor 2 (VEGFR-2) merupakan reseptor tirosin kinase yang berperan dalam angiogenesis. Pada beberapa kasus kanker ditemukan adanya overekspresi dari VEGFR-2. Agen penghambat VEGFR-2 memiliki potensi sebagai anti-angiogenesis yang diketahui memiliki potensi dalam menangani kanker. Senyawa flavonoid dilaporkan memiliki potensi sebagai penghambat tirosin kinase. Pada penelitian ini dilakukan untuk mencari senyawa turunan flavonoid dari genus Artocarpus yang memiliki potensi sebagai penghambat VEGFR-2. Penelitian ini dilakukan secara virtual skrining dengan metode penambatan molekul pada target protein VEGFR-2 (PDB ID: 4AG8) dengan menggunakan kontrol axitinib. Preparasi dilakukan dengan memisahkan ligan dari reseptor dan menghilangkan molekul air. Validasi dilakukan dengan menambatkan ligan pada reseptor untuk menghitung nilai RMSD dan menentukan koordinat penambatan. Penambatan senyawa uji dilakukan menggunakan koordinat dari hasil validasi. Visualisasi untuk melihat ikatan antara senyawa uji dan reseptor. Nilai RMSD sebesar 0,893 Å. Senyawa kanzonol C (ACP 51) memiliki energi ikatan terendah -10,6 kkal/mol, sedangkan energy ikatan pada kontrol (obat axitinib) sebesar -8,4 kkal/mol. Hasil visualisasi kanzanol C menunjukkan ikatan hidrogen pada Cys1045 dan Asp1046, interaksi hidrofobik meliputi pi-sigma Leu840, Lys868, Val916; alkil Leu889, Val899; pi-alkil Val848, Ala866, Leu1035, Phe1047. Senyawa kanzonol C (ACP 51) secara in silico merupakan hasil yang terbaik sebagai inhibitor VEGFR-2, dengan nilai energi terendah dibandingkan senyawa flavonoid lainnya

The role of P2Y₂ nucleotide receptors in vascular inflammation

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on March 12, 2008)Vita.Includes bibliographical references.Thesis (Ph. D.) University of Missouri-Columbia 2007.Dissertations, Academic -- University of Missouri--Columbia -- Biochemistry (Agriculture)Extracellular nucleotides act on P2 receptors to regulate vascular tone. Large amounts of extracellular nucleotides are released at the sites of tissue injury and may play an important role in the vascular inflammation. In vascular injury models, P2Y₂ mRNA was significantly up-regulated. Activation of up-regulated P2Y₂ receptors in the injured artery increased monocyte/macrophage infiltration and intimal hyperplasia. In this dissertation, we showed that activation of the P2Y₂ receptor modulates the expression of VCAM-1 in vascular endothelial cells that is important for monocyte recruitment. We report here that P2Y₂ receptor-induced VCAM-1 expression is mediated by rapid tyrosine phosphorylation of VEGFR-2 in HCAEC. RNA interference (RNAi) targeting of VEGFR-2 expression or inhibition of VEGFR-2 tyrosine kinase activity abolished P2Y₂ receptor-mediated VCAM-1 expression. We also discovered that the P2Y₂ receptor is linked to the cytoskeleton through direct interaction with the actin-binding protein filamin A (FLNa), which is a large protein of 280 kD and serves as a cross-linker of actin polymers and as a scaffolding protein for various signaling molecules. This interaction was mapped to the C-terminal tail of the P2Y2 receptor (amino acids 322 to 333) and is required for FLNa phosphorylation, spreading and migration of smooth muscle cells induced by extracellular nucleotides. These results encourage drug design targeting the P2Y₂ receptor as a means to prevent and/or treat arterial disease