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Articles by S Fleming
Total Records ( 2 ) for S Fleming
  M. A Nobrega , L. C Solberg Woods , S Fleming and H. J. Jacob
 

Goto-Kakizaki (GK) rats develop early-onset type 2 diabetes (T2D) symptoms, with signs of diabetic nephropathy becoming apparent with aging. To determine whether T2D and renal disease share similar genetic architecture, we ran a quantitative trait locus (QTL) analysis in the F2 progeny of a GK x Brown Norway (BN) rat cross. Further, to determine whether genetic components change over time, we ran the QTL analysis on phenotypes collected longitudinally, at 3, 6, 9 and 12 mo, from the same animals. We confirmed three chromosomal regions that are linked to early diabetes phenotypes (chromosomes 1, 5, and 10) and a single region involved in the late progression of the disorder (chromosome 4). A single region was identified for the onset of the renal phenotype proteinuria (chromosome 5). This region overlaps the diabetic QTL, although it is not certain whether similar genes are involved in both phenotypes. A second QTL linked to the progression of the renal phenotype was found on chromosome 7. Linkage for triglyceride and cholesterol levels were also identified (chromosomes 7 and 8, respectively). These results demonstrate that, in general, different genetic components control diabetic and renal phenotypes in a diabetic nephropathy model. Furthermore, these results demonstrate that, over time, different genetic components are involved in progression of disease from those that were involved in disease onset. This observation would suggest that clinical studies collecting participants over a wide age distribution may be diluting genetic effects and reducing power to detect true effects.

  X Liu , C. O. C Bellamy , M. A Bailey , L. J Mullins , D. R Dunbar , C. J Kenyon , G Brooker , S Kantachuvesiri , K Maratou , A Ashek , A. F Clark , S Fleming and J. J. Mullins
 

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.

 
 
 
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