The Role Of MMPs 1 And 9 And MT-1 MMP In Hormone Replacement Therapy Related Irregular Bleeding
Funder
National Health and Medical Research Council
Funding Amount
$294,625.00
Summary
Approximately 40% of women in Australia chose to take Hormone Replacement Therapy (HRT). This choice is usually based upon the perceived benefits of HRT such as the relief of debilitating menopausal symptoms (such as hot flushes and sweats), the prevention of brittle bone disease (osteoporosis) and the potential prevention of heart disease and memory loss (dementia). Unfortunately, many of these women (up to two thirds in a large UK study) then suffer from irregular bleeding. This is not only in ....Approximately 40% of women in Australia chose to take Hormone Replacement Therapy (HRT). This choice is usually based upon the perceived benefits of HRT such as the relief of debilitating menopausal symptoms (such as hot flushes and sweats), the prevention of brittle bone disease (osteoporosis) and the potential prevention of heart disease and memory loss (dementia). Unfortunately, many of these women (up to two thirds in a large UK study) then suffer from irregular bleeding. This is not only inconvenient, but raises anxiety that the bleeding may be a symptom of serious illness such as cancer of the womb. Many HRT users then undergo internal examinations, tests and operations to exclude cancer as the cause of the bleeding. In almost all cases no other abnormality is found. However, many women decide not to continue with HRT because of this troublesome bleeding. Very little is understood about the reason why women using HRT have irregular bleeding. Furthermore, there are no ways of predicting who will be affected and no established way to stopping or preventing bleeding apart from discontinuing HRT. This problem affects all HRT preparations. Previous pilot studies by the CI (Associate Professor Martha Hickey) have demonstrated for the first time that there are changes in the lining of the womb in women using HRT which may lead to bleeding. These are similar to changes seen in younger women with breakthrough bleeding using contraceptives. The planned project intends to futher explore the actions of the important molecules which break down the blood vessels of the womb lining (endometrium) and cause bleeding. This raises the possibility that specific agents could be developed to stop or prevent bleeding in HRT users. This is likely to substantially increase the acceptability of HRT and may thus have major positive health implications for women in Australia and worldwide.Read moreRead less
Regulation Of Endometrial Angiogenesis And Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$488,273.00
Summary
Unlike almost all other parts of the adult body, the blood vessels of the endometrium (lining of the uterus) grow and breakdown each month as part of the menstrual cycle. The endometrium also has a very unusual distribution of lymph vessels, which are responsible for removing excess fluid from the tissues and also have an important role in the immune system. The overall aim of this research is to understand how growth and regression of these vascular systems are controlled in the endometrium. Th ....Unlike almost all other parts of the adult body, the blood vessels of the endometrium (lining of the uterus) grow and breakdown each month as part of the menstrual cycle. The endometrium also has a very unusual distribution of lymph vessels, which are responsible for removing excess fluid from the tissues and also have an important role in the immune system. The overall aim of this research is to understand how growth and regression of these vascular systems are controlled in the endometrium. The information will have immediate relevance to a number of clinical problems in which abnormal changes in the blood and lymph vascular systems are observed (e.g. tumour growth, wound healing). This includes a number of significant problems relevant to women's health. Non-menstrual bleeding (often termed breakthrough bleeding) is one of the most common gynaecological problems suffered by women, and can be particularly worrying as it may be a symptom of more serious diseases such as uterine cancer. Breakthrough bleeding can occur under a wide range of hormonal conditions and is thought to be due, at least in part, to faulty uterine blood vessel growth. Endometrial cancer is another serious disease and is the most frequently diagnosed malignancy of the female reproductive system. When diagnosed early, this cancer responds well to therapy. However, treatment of this disease is much more difficult when an increase in blood vessel growth is observed and the tumours interact with the lymphatic vascular system. An aim of this research is to investigate changes in uterine blood and lymph vessel growth associated with breakthrough bleeding and endometrial cancer.Read moreRead less
Matrix Metalloproteinases, Leukocytes And Menstruation
Funder
National Health and Medical Research Council
Funding Amount
$191,812.00
Summary
Menstrual bleeding problems are a common cause of pain and discomfort for women and often are satisfactorily treated only by hysterectomy. Despite this, little is known about the processes causing menstruation. Recently, we and others have demonstrated a role for a family of biological catalysts (enzymes) which break down the structure of the tissue lining the uterus (the endometrium) and are thought to cause menstrual bleeding. However, the mechanisms regulating their production during the norm ....Menstrual bleeding problems are a common cause of pain and discomfort for women and often are satisfactorily treated only by hysterectomy. Despite this, little is known about the processes causing menstruation. Recently, we and others have demonstrated a role for a family of biological catalysts (enzymes) which break down the structure of the tissue lining the uterus (the endometrium) and are thought to cause menstrual bleeding. However, the mechanisms regulating their production during the normal menstrual cycle is still largely unknown. Cells which come initially from the blood (leukocytes, particularly neutrophils and eosinophils) dramatically increase in numbers immediately prior to menstruation and these along with other cells, known as mast cells, start to produce a number of factors which we postulate are important for regulation of the enzymes. These cells, are also present in high numbers in endometrium of women with menstrual bleeding problems. This study will demonstrate that both the enzymes, and the leukocytes play a critical role in menstruation and will determine how the leukocytes in the endometrium are regulated. The studies have important implications for understanding and treating menstrual bleeding disorders.Read moreRead less
Excessive menstrual bleeding (menorrhagia) affects the health and quality of life of 1 in 3 women. There are also significant economic issues due to treatment costs and absence from work. Current medical therapies are insufficient or associated with side-effects and many women instead choose surgery (hysterectomy). The overall aim of our research is to elucidate the molecular mechanisms responsible for heavy menstrual bleeding and to determine how medical therapies can be better directed at indi ....Excessive menstrual bleeding (menorrhagia) affects the health and quality of life of 1 in 3 women. There are also significant economic issues due to treatment costs and absence from work. Current medical therapies are insufficient or associated with side-effects and many women instead choose surgery (hysterectomy). The overall aim of our research is to elucidate the molecular mechanisms responsible for heavy menstrual bleeding and to determine how medical therapies can be better directed at individual women.Read moreRead less
Novel Roles For Follistatin In Reproductive Biology
Funder
National Health and Medical Research Council
Funding Amount
$630,916.00
Summary
The follistatin protein has important functions throughout the body. Recent studies using mutant mice have identified key roles for follistatin in the development and function of the female reproductive system (ovary, uterus). We will now undertake detailed studies to determine how follistatin regulates these processes. This is relevant to our understanding of the mechanisms causing infection and inflammation in the reproductive tract.
Novel Selective Anti-platelet And Clot-specific Anticoagulant Strategies Targeting Conformational States Of GPIIb/IIIa
Funder
National Health and Medical Research Council
Funding Amount
$496,517.00
Summary
The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding compl ....The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding complications are also a major financal burden for our health care system. Thus, progress towards therapeutic strategies with less bleeding complications is highly sought-after. The proposed project aims to generate new antibody-based agents for platelet inhibition. One group of these agents do only block platelets when they are activated. Furthermore, these agents allow an enrichment of potent inhibitors of coagulation factors at the site of the clot. Thus, these inhibitors should predominatly act at the site where they are needed. At the same time the overall concentration of inhibitors of coagulation factors can be kept low and the functions of non-activated platelet can be left intact. Overall, the proposed project aims for the development of novel anti-platelet and anticoagulant strategies with high anti-thrombotic efficacy and low bleeding risks.Read moreRead less
Molecular Characterization Of The Gingipains Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$394,000.00
Summary
Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic perio ....Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic periodontitis. We have identified a major virulence factor of P. gingivalis which is an extracellular complex of proteins involved in binding and destroying host proteins. The aim of this proposal is to characterize the secretion, molecular processing and assembly of the cell surface complex using state-of-the-art proteomic techniques. This study will provide valuable insight into the molecular processes of a bacterial pathogen that leads to virulence. Detailed knowledge on the unique molecular events involved in secretion, processing and assembly of a major virulence factor will provide molecular targets for the development of specific inhibitors that may have utility as an adjunctive therapeutic and-or as part of a preventive regime or maintenance program for the control of chronic periodontitis. Further, the molecular insight that will result from this study will have broader application in the understanding of virulence factor processing of a Gram-negative pathogen that will provide paradigms for other bacterial pathogens.Read moreRead less