Objective
IN VIVO OR IN VITRO MULTIHORMONAL RESPONSE HAVE BEEN USED AS A PRESCREENING TEST FOR ASSESSING THE BIOLOGICAL ACTIVITY OF DRUG WHOSE MECHANISM OF ACTION IS STILL UNELICIDATED. A BETTER UNDERSTANDING OF THOSE RESPONSES IN TERMS OF RECEPTOR COUPLING MECHNISMS REQUIRES COMPLEMENTARY EXPERIMENTS AIMED AT :A) INVESTIGATING THE SELECTIVITY OF A GIVEN CLASS OF DRUGS ON HORMONE RESPONSES, AND B) CHARACTERIZING ITS MECHANISM OF ACTION ON 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. GILLHAM'S GROUP IS ABLE TO PERFUSE THE WHOLE TISSUE VIA THE VASCULATURE, WHILST DR. KORDON'S GROUP HAS REFINED THE USE OF TISSUE SLICES.IT WILL TEHREFORE 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 DETERMINED BY RIA ARE : LONDON - CRF (ALSO BY TWO-SITE IRMA) AND LHRH; PARIS - SOMATOSTATIN AND ALSO METENKEPHALIN. SAMPLES GENERATED BY THE USE OF THE PERFISED PITUITARY COLUMN TECHNIQUE DEVELOPED BY DR.GILLHAM'S GROUP WILL BE ANALYSED FOR A RANGE OF PITUITARY HORMONES : LONDON - ATCH, LH; PARIS - GH, PROLACTIN. 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 INVESTIGATED WILL BE CALCIUM/CALMODULIN (PARIS) AND POLYAMINES (LONDON) WITH PARTICULAR STRESS BEING PLACED ON INTERACTIONS BETWEEN THE TWO.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- natural sciences biological sciences biochemistry biomolecules proteins
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Coordinator
SE1 7EH London
United Kingdom
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