Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t ....Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.Read moreRead less
Focimatrix Regulation Of Sex Steroid Hormones In The Ovary
Funder
National Health and Medical Research Council
Funding Amount
$291,309.00
Summary
Sex steroid hormones (e.g. oestrogen and testosterone), are important to male and female health. In the ovarian follicle I identified a novel form of extracellular matrix (focimatrix) which develops in the ovary before the synthetic enzymes needed for sex steroids are present. Using evidence from other tissues, I developed ideas on how this matrix regulates the enzymes for hormone synthesis. I will examine a mechanism by which focimatrix could directly affect steroid hormone production.
The steroid hormone aldosterone controls salt balance and hence, blood pressure. It also has been shown to have a significant role in cardiac failure. Although drugs that block the aldosterone receptor are beneficial in the treatment of heart failure, they are limited by potassium retention in the kidney. In order to develop tissue-specific blockers of the aldosterone receptor, it is necessary to identify mechanisms by which the receptor can be activated and/or blocked in these tissues.
Identification Of Regulatory Protein Interactions On The CRH Promoter
Funder
National Health and Medical Research Council
Funding Amount
$216,600.00
Summary
CRH made in the brain controls our response to stress, and when made by the placenta it controls when birth will occur. Changes to the stress response can have important implications in heart disease, cancer, obesity and many other diseases. 70% of neonatal death is a result of premature birth, and pre-term babies that survive are more likely to have intellectual handicap or cerebral palsy. This research will help us understand CRH production during stress and pregnancy.
Molecular Regulation Of CRH Gene Expression In The Human Placenta
Funder
National Health and Medical Research Council
Funding Amount
$70,285.00
Summary
Approximately 70% of infant death is a result of premature birth. Preterm delivery occurs in 6-10% of pregnancies, and there has been no reduction in this rate in the last 30 years. This is largely because we remain ignorant of how normal and preterm birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotropin releasing hormon ....Approximately 70% of infant death is a result of premature birth. Preterm delivery occurs in 6-10% of pregnancies, and there has been no reduction in this rate in the last 30 years. This is largely because we remain ignorant of how normal and preterm birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotropin releasing hormone, CRH) in the placenta and the length of time the baby is carried in the mother. In women who will deliver prematurely the rise in CRH production occurs earlier and more rapidly, while in women who deliver late the rise occurs more slowly. This work has led to the concept of a biological clock that determines the length of time the fetus will be carried by the mother before birth, and in which production of CRH in the placenta plays a central role. We have been studying how the CRH gene is controlled in placental cells. We have discovered some regions in the DNA of the CRH gene which have important roles in controlling how much CRH is made by the placenta. The experiments described in this project will determine the molecular mechanisms that control the production of CRH in the human placenta. This will be done by examining the DNA sequences involved in controlling the CRH gene and by identifying the proteins that actually perform the regulating functions that result in either increased or decreased amounts of CRH being produced by the placenta. This important information will help us better understand how normal and preterm birth is controlled, and from that knowledge new ways to detect and prevent premature birth can be developed.Read moreRead less
Impact Of Progesterone Receptor Subnuclear Localisation On Progesterone Action In Endocrine Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$459,514.00
Summary
Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We ....Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We have noticed that in cancers, this accumulation is disrupted, and this is a bad sign for the cancer. As breast cancer develops, it causes many dramatic changes in the structure of cells of the breast, and particularly in the nucleus, which carries the genetic information that programs cancer cell behaviour. The nucleus normally is highly organised into compartments, which carry out different functions of the cell, such as duplication of the DNA, repair of DNA after damage, and switching on and off of particular genes important to the function of the cell. This organisation is altered dramatically in cancer cells, and it seems that this altered organisation is responsible for altered function. In this project we aim to work out what makes the receptor for progesterone form foci, how these foci are involved in the action of progesterone, and how the changed structure of the nucleus changes this process. This project will link the structure of the cell nucleus with the ability of progesterone to switch on or off particular genes, and this will provide the first signposts of how changes seen in cancer cell nuclei are reflected in changed hormonal signalling. Healthy women are regularly exposed to progestins in oral contraceptives and hormone replacement therapy. The known increased risk of breast cancer as a result of exposure to progestins creates an imperative to understand how progesterone may have aberrant effects. This project will address this important health issue.Read moreRead less
Molecular Characterisation Of Steroid Hormone-dependent Diseases Of The Cardiovascular And Reproductive Systems
Funder
National Health and Medical Research Council
Funding Amount
$1,085,790.00
Summary
Peter Fuller is both a molecular and clinical endocrinologist. His research examines steroid hormones in cardiovascular disease and cancer. The hormone aldosterone controls blood pressure and has a significant role in cardiac failure. This work will enable the development of tissue-specific blockers of aldosterone for the treatment of cardiovascular disease. Steroid hormones also have a role in granulosa cell tumours of the ovary and breast cancer; new insights will lead to novel therapeutics.
Progesterone Signalling In Normal And Malignant Breast Relies On Chromosomal Positioning Of Progesterone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$569,346.00
Summary
The cell nucleus carries genetic information that directs cell function. The nucleus is organised into compartments, which are altered in breast cancer, leading to altered function. The ovarian hormone progesterone acts via a receptor, which clumps into foci in the nucleus when active. In cancers, this clumping is disrupted. In this project we will work out how these foci control cell function, and how this leads to the specific functions of progesterone in normal breast and breast cancers.
Progesterone Regulation Of Epithelial Cell Lineages In The Breast
Funder
National Health and Medical Research Council
Funding Amount
$534,186.00
Summary
The ovaries play a pivotal role in breast cancer in ways that are unknown. Progesterone increases breast cancer risk, and response to hormonal treatments is critically associated with tumour progesterone receptor content, but how it does this is unknown. We will pursue our findings that progesterone influences cell types in the breast similar to those that become cancerous. This will uncover critical vulnerabilities in breast cancer development and potential targets for prevention and treatment.
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.