A major goal of this Project is to identify biochemical and molecular parameters that correlate with the development of hypertension in spontaneously hypertensive rats (SHR) and could therefore be used to follow the segregation of hypertension causing genes in SHRxWKY F2 progeny and SHRxBN recombinant inbred strains. A second major goal of this unit is to identify molecular mechanisms involved in modulation of gene expression in response to target organ damage. The basic working hypothesis guiding this unit and examined by it is that stress activated protein kinases, such as JNK, play major roles in modulating cellular gene expression and phenotypes in response to stresses such as pressure overland and ischemia- reperfusion. These protein kinases carry out such functions through phosphorylation of various components and regulators of transcription factors AP-l and NK-kB, as well as regulatory proteins, such as the Na+/H+ exchanger. The same signaling pathways can also affect the proliferation of smooth muscle cells and fibroblasts and control the deposition of extracellular matrix. These signaling pathways linking extracellular events to the control of gene transcription and cellular homeostasis could therefore be of importance both in affecting the development of hypertension in response to external stress and in mediating target organ damage in response to hypertension and pressure overload. To follow these general goals and test its working hypothesis, this unit will pursue the following specific aims: 1) Elucidate the signal transduction pathways that lead to activation of stress responsive protein kinases and transcription factors following ischemia-reperfusion; 2) Determine which mitogen activated protein kinase (MAPK) family member is responsible for phosphorylation and stimulating the activity of the Na+/H+ exchanger; 3) Compare the activities of different MAPKs and stress regulated transcription factors in cardiac fibroblasts and myocytes derived from the WKY(LJ) and SHR(LJ) strains and use segregation analysis in collaboration with Projects 1 and 2 and Core C to determine the significance of such changes; 4) Determine the mechanisms by which thrombin, bradykinin and angiotensin II can stimulate JNK and p38 activities; 5) Generate mouse strains defective in the different MAPK signaling pathways to test their involvement in hypertension.
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