Global ETD Search

11	Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension Nasim, Md. Talat, Ogo, T., Ahmed, Mohammed I., Randall, R., Chowdhury, H.M., Snape, K.M., Bradshaw, T.Y., Southgate, L., Lee, G.J., Jackson, I., Lord, G.M., Gibbs, J.S., Wilkins, M.R., Ohta-Ogo, K., Nakamura, K., Girerd, B., Coulet, F., Soubrier, F., Humbert, M., Morrell, N.W., Trembath, R.C., Machado, R.D. January 2011 (has links) Yes / Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease. Bone morphogenetic protein receptors Type II Genetics Cohort studies Female Gene expression regulation Humans Hypertension Pulmonary Male Sequence analysis DNA Signal transduction Smad1 protein Smad8 protein Transcriptional regulation REF 2014
12	BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH Nasim, Md. Talat, Ogo, T., Chowdhury, H.M., Zhao, L., Chen, C-n., Rhodes, C., Trembath, R.C. January 2012 (has links) Yes / Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH. Animals Apoptosis Bone morphogenetic protein receptors Type II Metabolism Cell proliferation Cells Cultured Hypertension Pulmonary Pathology MAP kinase Mice Pulmonary artery Rats Signal transduction Transforming growth factor beta REF 2014
13	Making sense of smell : classifications and model thinking in olfaction theory Barwich, Ann-Sophie January 2013 (has links) This thesis addresses key issues of scientific realism in the philosophy of biology and chemistry through investigation of an underexplored research domain: olfaction theory, or the science of smell. It also provides the first systematic overview of the development of olfactory practices and research into the molecular basis of odours across the 19th and 20th century. Historical and contemporary explanations and modelling techniques for understanding the material basis of odours are analysed with a specific focus on the entrenchment of technological process, research tradition and the definitions of materiality for understanding scientific advancement. The thesis seeks to make sense of the explanatory and problem solving strategies, different ways of reasoning and the construction of facts by drawing attention to the role and application of scientific representations in olfactory practices. Scientific representations such as models, classifications, maps, diagrams, lists etc. serve a variety of purposes that range from the stipulation of relevant properties and correlations of the research materials and the systematic formation of research questions, to the design of experiments that explore or test particular hypotheses. By examining a variety of modelling strategies in olfactory research, I elaborate on how I understand the relation between representations and the world and why this relation requires a pluralist perspective on scientific models, methods and practices. Through this work I will show how a plurality of representations does not pose a problem for realism about scientific entities and their theoretical contexts but, on the contrary, that this plurality serves as the most reliable grounding for a realistic interpretation of scientific representations of the world and the entities it contains. The thesis concludes that scientific judgement has to be understood through its disciplinary trajectory, and that scientific pluralism is a direct consequence of the historicity of scientific development. 612.86
14	Bone morphogenetic proteins differentially regulate pigmentation in human skin cells Singh, Suman K., Abbas, Waqas A., Tobin, Desmond J. January 2012 (has links) No / Bone morphogenetic proteins (BMPs) are a large family of multi-functional secreted signalling molecules. Previously BMP2/4 were shown to inhibit skin pigmentation by downregulating tyrosinase expression and activity in epidermal melanocytes. However, a possible role for other BMP family members and their antagonists in melanogenesis has not yet been explored. In this study we show that BMP4 and BMP6, from two different BMP subclasses, and their antagonists noggin and sclerostin were variably expressed in melanocytes and keratinocytes in human skin. We further examined their involvement in melanogenesis and melanin transfer using fully matched primary cultures of adult human melanocytes and keratinocytes. BMP6 markedly stimulated melanogenesis by upregulating tyrosinase expression and activity, and also stimulated the formation of filopodia and Myosin-X expression in melanocytes, which was associated with increased melanosome transfer from melanocytes to keratinocytes. BMP4, by contrast, inhibited melanin synthesis and transfer to below baseline levels. These findings were confirmed using siRNA knockdown of BMP receptors BMPR1A/1B or of Myosin-X, as well as by incubating cells with the antagonists noggin and sclerostin. While BMP6 was found to use the p38MAPK pathway to regulate melanogenesis in human melanocytes independently of the Smad pathway, p38MAPK, PI3-K and Smad pathways were all involved in BMP6-mediated melanin transfer. This suggests that pigment formation may be regulated independently of pigment transfer. These data reveal a complex involvement of regulation of different members of the BMP family, their antagonists and inhibitory Smads, in melanocytes behaviour. Adult Aged Bone Morphogenetic Protein 4 Antagonists & inhibitors Metabolism Pharmacology Bone Morphogenetic Protein 6 Antagonists & inhibitors Metabolism Pharmacology Bone Morphogenetic Protein Receptors Coculture techniques Epidermis Drug effects Radiation effects Female Gene knockdown techniques Humans Keratinocytes Enzymology Melanins Biosynthesis Melanocytes Ultrastructure Middle aged Models Biological Monophenol Monooxygenase Myosins Pigmentation Pseudopodia Signal transduction Skin cytology Smad Proteins Ultraviolet rays Up-Regulation p38 Mitogen-Activated Protein Kinases REF 2014

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