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  • The physiological function of the Renin Angiotensin Aldosterone System is to maintain volume and electrolyte homeostasis and to set blood pressure. Angiotensin II, the most active effector substance of the RAAS, is formed in a cascade triggered by the release of renin from the kidneys; Increase plasma ANG II in turn stimulates the adrenal cortex to secrete the mineralocorticoid aldosterone. Alternatively an increase in extracellular potassium can also stimulate the adrenal cortex to release aldosterone. Upon release from the adrenal cortex, aldosterone binds to the mineralcorticoid receptor The classical mineralocorticoid effects of aldosterone are those observed in epithelial tissues such as the kidney and colon In these tissues aldosterone increase sodium reabsorption and potassium secretion thus maintaining cardiovascular homeostasis Mineralocorticoid receptors are have also been identified in non-classical, non-epithelial target tissue such as the hippocampus, vascular smooth muscle cells (VSMC), and heart. Aldosterone binding to MR receptors in these tissues has cardiovascular system pathophysiological consequences such as Hypertension, cardiac hypertrophy and fibrosis
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    1. 1. Prince Henry’s Institute of Medical Research
    2. 2. Molecular genetic pathway of human sex determination Vince Harley Embryonic gonad at 6 weeks & 7 weeks gestation SRY testis ovary SOX9 XY XX Swyer Syndrome …. Campomelic Dysplasia …. What genes do SRY and SOX9 turn on and how? Are SRY/SOX9 target genes intersex genes? What is the molecular effect of clinical SRY/SOX9 mutations? QUESTIONS: Molecular biology, cell biology, protein biochemistry human intersex patients, human EC lines, mouse knockouts, TECHNIQUES & reagents
    3. 3. Female Reproductive Endocrinology Group: Prof. Jock Findlay, Dr Ann Drummond, Dr Paul Farnworth Progesterone receptors Androgen Primary Primordial Secondary Preovulatory Corpus luteum LH receptors Granulosa cell Atresia Developing Follicles Ovulation Theca (androgens) Oocyte (progesterone estrogen) Androgen Oestrogen FSH receptors
    4. 4. The hormonal regulation of sperm production: David Robertson, Dr Peter Stanton, Dr Sarah Meachem, Prof Rob MacLaclan Why are we interested?  to understand the process of sperm production (spermatogenesis) in the healthy male  to apply this knowledge to the development of treatments for male infertility  to devise effective and reversible hormonal contraceptives for men
    5. 5. E 2 <ul><li>Techniques </li></ul><ul><li>cell culture </li></ul><ul><li>transfection </li></ul><ul><li>RNA analysis </li></ul><ul><li>DNA / protein interaction </li></ul>Breast cancer and estrogens: Prof Evan Simpson, Dr Colin Clyne
    6. 6. <ul><li>Male reproductive system </li></ul><ul><li>Dietary studies </li></ul><ul><li>Adiposity </li></ul><ul><li>Female reproductive system </li></ul>The Aromatase knockout (ArKO) mouse <ul><li>Brain </li></ul>Prof Evan Simpson, Dr Margaret Jones
    7. 7. Endocrine Cell Biology: Dr Chen Chen <ul><li>Type-II diabetes – approx. 1 million Australians </li></ul><ul><ul><li>influence of adipocyte-derived factors on pancreatic  -cells </li></ul></ul><ul><ul><li>co-culture b-cells with fat cells </li></ul></ul><ul><li>GH deficiency in ageing population </li></ul><ul><ul><li>pituitary somatotropes in ArKO mice </li></ul></ul><ul><li>O besity and GH deficiency </li></ul><ul><ul><li>leptin-from fat, orexin-from CNS, and ghrelin-from stomach . </li></ul></ul>
    8. 8. Uterine Biology Group <ul><li>Mission: to improve women’s health by- </li></ul><ul><li>Increasing contraceptive choices for women </li></ul><ul><li>Improving fertility of infertile women </li></ul><ul><li>Reducing / treating uterine bleeding problems </li></ul>Prof Lois Salamonsen, Dr Eva Dimitriadis, Dr Guiying Nie, Dr Naomi Morrison NP d3.5 Imp Inter Imp Inter d4.5 d5.5
    9. 9. 1. Granulosa Cell Tumours (GCT) <ul><li>5% of malignant ovarian tumours </li></ul><ul><li>Approach: tumour bank and cell lines </li></ul><ul><li>Our focus has been on: </li></ul><ul><li>profiles of gene expression: candidates & microarray </li></ul><ul><li>signalling pathways – constitutive activation </li></ul><ul><li>expression of ER  </li></ul><ul><ul><ul><li>coregulatory molecules </li></ul></ul></ul><ul><ul><ul><li>ER β -induced genes </li></ul></ul></ul><ul><li>mutation detection </li></ul>Prof Peter Fuller
    10. 10. 2. Mineralocorticoid Receptor Structure-Function Projects <ul><li>ligand binding specificity </li></ul><ul><li>interdomain interactions </li></ul><ul><li>coregulatory proteins </li></ul>Prof Peter Fuller
    11. 11. 3. Mineralocorticoids and heart disease Hypertension Hypertrophy Vascular Inflammation Cardiac Fibrosis Aldosterone ↑ Extracellular Potassium Fluid and electrolyte homeostasis MR RAAS In 2002, CVD claimed the lives of 50,000 Australians (~40% of all deaths) Heart failure accounts for many of these deaths Prof Peter Fuller and Dr Morag Young
    12. 12. PRINCE HENRY’S INSTITUTE STUDENT OPEN DAY Come and meet our researchers and take a tour of our facilities Tuesday 8 AUGUST 2006 10am – 12pm Friday 11 AUGUST 2006 1pm – 3pm Prince Henry’s Institute Level 4 43 – 51 Kanooka Grove Clayton VIC 3168
    13. 13. Experimental approach es <ul><li>Molecular biology : RT-PCR , RNAi (reduced expression) and transfection (over-expression) ; </li></ul><ul><li>Histochemistry : receptor and ligand localisation; </li></ul><ul><li>Patch clamp : ion channel and electrophysiology; </li></ul><ul><li>[Ca 2+ ] i : microphotometric recording for real-time and confocal microscope for spatial distribution; </li></ul><ul><li>Exocytosis : single cell-fluorescent Zinc (Insulin), capacitance, amperometry; population-RIA . </li></ul>