This Clinical Investigator Award proposal originates from a young investigator who has completed her training in Clinical Nephrology and who has also spent 3 years in a well focused area of investigative nephrology. The proposed studies are a logical extension of the observations made by the applicant during her research training in the pathophysiology of renal immune injury. These observations have defined mediators of the renal hemodynamic perturbations occurring following mesangial cell injury induced by antibody against the mesangial cell antigen Thy 1.1 which results in renal failure and proliferative nephritis. In this model of human mesangial nephropathies, the applicant has demonstrated that antibody binding to the mesangial cell Thy 1.1 antigen induces acute decrements in glomerular filtration rate and its determinant, the ultrafiltration coefficient Kf. These decrements are associated with enhanced glomerular synthesis of the vasoactive eicosanoids, thromboxane (Tx) A2, leukotriene (LT) B4 and 12-hydroxyeicosatetraenoic acid (HETE), of which TxA2 specifically mediates the decrements in GFR. It was also demonstrated that activation of the complement system mediates the increments in these eicosanoids and the decrements in GFR. Moreover, it was shown that the cell origin of these eicosanoids may not be the injured mesangial cell only. They may also originate from hematogenous inflammatory cells (platelets, leukocytes) an observation which raises the possibility that eicosanoids mediate renal hemodynamic perturbations via a paracrine effect on mesangial cells. The proposed studies place a central role on the eicosanoids: TxA2, LTB4, and 12-HETE as mediators of the vasoactive phenomena occurring following mesangial cell injury and will identify their cell origin, their mechanism of synthesis and the signalling events and biomechanical responses they induce on mesangial cells. The methods involve the use of: lipid biochemistry to identify eicosanoids and signalling molecules, whole organ (kidney) and mesangial cell physiology to characterize the vasoactive events and underlying cell responses, and immunopathology to identify the immune reactants which initiate the mesangial cell injury and to draw structural-functional correlations. The proposed studies will be pursued in an environment which provides all the infrastructure and methodologic resources necessary and under the guidance of two sponsors with established track records in the biology of renal immune injury and in renal physiology both at the whole organ and the cellular level. It is, therefore, anticipated that the expertise derived from this Award will be instrumental for the applicant to conceptualize and pursue an independent direction in investigative nephrology.
| Breshnahan, B A; Kelefiotis, D; Stratidakis, I et al. (1996) PGF2alpha-induced signaling events in glomerular mesangial cells. Proc Soc Exp Biol Med 212:165-73 |
| Kelefiotis, D; Bresnahan, B A; Stratidakis, I et al. (1995) Eicosanoid-induced growth and signaling events in rat glomerular mesangial cells. Prostaglandins 49:269-83 |
