KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース)

Tissue engineering aims at developing functional substitutes for damaged tissues and organs. Before transplantation, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix and provide cells with information that is important for tissue development. Here we review the nanocomposite nature of the extracellular matrix, describe the design considerations for different tissues and discuss the impact of nanostructures on the properties of scaffolds and their uses in monitoring the behaviour of engineered tissues. We also examine the different nanodevices used to trigger certain processes for tissue development, and offer our view on the principal challenges and prospects of applying nanotechnology in tissue engineering.

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Nanotechnological strategies for engineering complex tissues.

Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear-cell renal carcinomas. The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation of hypoxia-inducible factor (HIF), plays a central role in the mammalian oxygen-sensing pathway. This interaction between pVHL and HIF is governed by post-translational prolyl hydroxylation of HIF in the presence of oxygen by a conserved family of Egl-nine (EGLN) enzymes. In the absence of pVHL, HIF becomes stabilized and is free to induce the expression of its target genes, many of which are important in regulating angiogenesis, cell growth, or cell survival. Moreover, preliminary data indicate that HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) might one day play a role in the treatment of hemangioblastoma and renal cell carcinoma. On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF.

Role of VHL Gene Mutation in Human Cancer

The von Hippel-Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel-Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.

Molecular basis of the VHL hereditary cancer syndrome

https://www.cell.com/cell-metabolism/pdf/S1550-4131(10)00153-1.pdf

With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging.

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Nightshade Prototype Experiments (Silverleaf)

Cells are a natural unit of abstraction for tissue morphogenesis. Cell-based theoretical models provide a platform for determining key elements of cell behavior responsible for multicellular and tissue-level phenomena, and for integrating molecular and tissue/organ scales. This chapter reviews a limited selection of recent developments in cell-based modeling approaches to angiogenesis. We offer an introduction to building a cell-based model with an emphasis on model validation, and illustrate this model building process in tumor angiogenesis using the cellular Potts model.

Cell-Based Models of Tumor Angiogenesis

/pdf/silverleaf-an-experimental-series-in-support-of-nightshade-3xg3efstt0.pdf

Silverleaf: An Experimental Series in Support of Nightshade

Cancer invasion and metastasis depend on angiogenesis The cellular processes (growth, migration, and apoptosis) that occur during angiogenesis are tightly regulated by signaling molecules Thus, understanding how cells synthesize multiple biochemical signals initiated by key external stimuli can lead to the development of novel therapeutic strategies to combat cancer In the face of large amounts of disjoint experimental data generated from multitudes of laboratories using various assays, theoretical signal transduction models provide a framework to distill this vast amount of data Such models offer an opportunity to formulate and test new hypotheses, and can be used to make experimentally verifiable predictions This study is the first to propose a network model that highlights the cross-talk between the key receptors involved in angiogenesis, namely growth factor, integrin, and cadherin receptors From available experimental data, we construct a stochastic Boolean network model of receptor cross-talk, and systematically analyze the dynamical stability of the network under continuous-time Boolean dynamics with a noisy production function We find that the signal transduction network exhibits a robust and fast response to external signals, independent of the internal cell state We derive an input-output table that maps external stimuli to cell phenotypes, which is extraordinarily stable against molecular noise with one important exception: an oscillatory feedback loop between the key signaling molecules RhoA and Rac1 is unstable under arbitrarily low noise, leading to erratic, dysfunctional cell motion Finally, we show that the network exhibits an apoptotic response rate that increases with noise, suggesting that the probability of programmed cell death depends on cell health

Amy L. Bauer

Papers

Nightshade Prototype Experiments (Silverleaf)

Cell-Based Models of Tumor Angiogenesis

Silverleaf: An Experimental Series in Support of Nightshade

Stochastic Network Model of Receptor Cross-Talk Predicts Anti-Angiogenic Effects