Cel IN VIVO OR IN VITRO MULTIHORMONAL RESPONSES HAVE BEEN USED AS A PRESCREENING TEST FOR ASSESSING THE BIOLOGICAL ACTIVITY OF DRUGS WHOSE MECHANISM OF ACTION IS STILL UNELUCIDATED. A BETTER UNDERSTANDING OF THOSE RESPONSES IN TERMS OF RECEPTOR COUPLING MECHANISMS REQUIRES COMPLEMENTARY EXPERIMENTS AIMED AT : A) INVESTIGATING THE SELECTIVITY OF A GIVEN CLASS OF DRUGS ON HORMONES RESPONSES, AND B) CHARACTERIZING ITS MECHANISM OF ACTION OR ITS POST-RECEPTOR COUPLING PROCESSES. Hormone response pathways involved in the production of prolactin (PRL) and corticotrophin (ACTH) have been studied using in vitro preparations of hypothalamic and pituitary tissues (blocks, slices, primary cultures and tumour cell lines). Ion channels were studied both electrophysiologically and pharmacologically and second messenger responses were assessed in several ways, including the use of in situ hybridisation to measure messenger ribonucleic acid (mRNA) and high performance liquid chromatography (HPLC) to assess events relating to protein synthesis. A hormone regulated, voltage sensitive calcium channel in lactotrophs was confirmed by direct electrophysiological observation and activation of this channel was shown to entrain increases in the mRNA for PRL. In addition, the activity of the channel was shown to be controlled in a negative sense by a G protein, an effect opposed by the steroid hormone oestradiol. Closer examination of the G protein mechanism showed that it is possible to desynchronise secretory and transcriptional responses to neurotransmitter stimulation in lactotrophs. The synthetic glucocorticoid dexamethasone was found to interfere acutely with another G protein dependent event, the late processing of the ACTH molecule. On the other hand, glucocorticoids chronically caused a profound reduction in the mRNA for ACTH. Thus a series of both rapid and delayed intracellular changes are initiated by hormones and neurotransmitters and these may readily be assessed by the application of appropriate techniques.THE TWO GROUPS HAVE DEVELOPED COMPLEMENTARY PREPARATIONS FOR THE STUDY OF HYPOTHALAMIC FUNCTION IN VITRO.DR.JONE'S GROUP IS ABLE TO PERFUSE THE WHOLE TISSUE VIA THE VASCULATURE, WHILST DR.KORDON'S GROUP HAD REFINED THE USE OF TISSUE SLICES AND CULTURE OF PITUITARY CELLS, OF GLIAL CELLS AND OF NEURONS. IT WILL THEREFORE BE POSSIBLE TO COMPARE RESULTS OBTAINED WITH THE TWO PREPARATIONS AND THUS TO DEVELOP A MORE SOPHISTICATED MODEL OF THE CONTROL OF THE ENDOCRINE FUNCTION OF THE HYPOTHALAMUS BY BOTH INTER- AND INTRA-CELLULAR MESSENGERS.THE HYPOTHALAMIC HORMONES TO BE DETEMINED BY RIA ARE : LONDON - CRF (ALSO BY TWO-SITE IRMA), LHR AND GRF; PARIS - SOMASTATIN AND ALSO METENKEPHALIN.SAMPLES GENERATED BY THE USE OF THE PERFUSED PITUITARY COLUMN TECHNIQUE DEVELOPED BY DR.JONE'S GROUP WILL BE ANALYSED FOR A RANGE OF PITUITARY HORMONES : LONDON - ACTH, LH; PARIS -GH, PROLACTING. ONCE AGAIN, EMPHASIS WILL BE PLACED ON SECOND MESSENGER SYSTEMS AND THE COUPLING OF SPECIFIC RECEPTORS TO THE ACTIVATION OF SUCH SYSTEMS. THE MAJOR SECOND MESSENGER SYSTEMS TO BE INVESTAGATED WILL BE CALCIUM/CALMODULIN (PARIS) AND POLYAMINES (LONDON) WITH PARTICULAR STRESS BEING PLACED ON INTERACTIONS BETWEEN THE TWO. Dziedzina nauki natural scienceschemical sciencesinorganic chemistryalkaline earth metalsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteins Program(-y) FP1-BAP - Multiannual research action programme (EEC) in the field of biotechnology (BAP), 1985-1989 Temat(-y) Data not available Zaproszenie do składania wniosków Data not available System finansowania CSC - Cost-sharing contracts Koordynator INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE Wkład UE Brak danych Adres Rue de Tolbiac, 101 75654 PARIS Francja Zobacz na mapie Koszt całkowity Brak danych Uczestnicy (1) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko St Thomas's Hospital Medical School Zjednoczone Królestwo Wkład UE Brak danych Adres Lambeth Palace Road London Zobacz na mapie Koszt całkowity Brak danych
