Structure-function And Domain Minimization Of Insulin-like Peptide 3, A Novel Member Of The Insulin Superfamily.
Funder
National Health and Medical Research Council
Funding Amount
$288,000.00
Summary
Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selectio ....Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.Read moreRead less
The Structural Basis Of The Interaction Of Insulin-like Peptide 3, A Key Regulator Of Fertility, With Its Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
The hormone, insulin-like peptide 3, has recently been shown to act directly on male and female germ cells to cause their maturation. It has considerable promise as a therapeutic agent for the regulation of fertility. Drugs based on the peptide may be used to assist in cases of infertility, and drugs that block its action have great potential as male and female contraceptives. Towards these goals, our project aims to understand how this peptide exerts its unique biological effects.
Role Of Insulin-like Growth Factor Binding Protein-3 As A Mediator Of Apoptosis In Human Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$352,234.00
Summary
Human breast cancer, like other human cancers, is characterised by a disruption of normal cellular growth due to defects in the control of both cell proliferation and cell death. Understanding how these processes are regulated in normal and cancerous breast cells is an important goal for breast cancer treatment. Insulin-like growth factor binding protein (IGFBP)-3 is a regulator of normal and cancerous breast cell growth and has been implicated as a negative prognostic indicator for breast cance ....Human breast cancer, like other human cancers, is characterised by a disruption of normal cellular growth due to defects in the control of both cell proliferation and cell death. Understanding how these processes are regulated in normal and cancerous breast cells is an important goal for breast cancer treatment. Insulin-like growth factor binding protein (IGFBP)-3 is a regulator of normal and cancerous breast cell growth and has been implicated as a negative prognostic indicator for breast cancer progression. IGFBP-3 inhibits the growth of breast cancer cells and causes them to die by a process called apoptosis. We are determining how IGFBP-3 causes breast cancer cells to die by apoptosis. In particular, we are investigating whether IGFBP-3 may make breast cancer cells more sensitive to the apoptotic effects of ionising radiation and chemotherapeutic drugs which are both current therapies for the treatment of breast carcinoma. These studies may, in turn, elucidate the mechanisms that lead to increased resistance of breast cancers to these treatments.Read moreRead less
This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzz ....This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzzles of the anatomical differences between males and females.Read moreRead less
In 2011 there were over 360 million people with type 1 and type 2 diabetes worldwide, who will require insulin treatment. There is an urgent need for insulin analogues that provide effective control of blood glucose to avoid unwanted hypoglycemic or hyperglycemic events. We have developed two novel insulin analogues with unique properties and aim to understand their mechanism of action. This knowledge will present new opportunities for improved insulin mimetics for diabetes treatment.
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Sensitivity And Signalling In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$414,343.00
Summary
The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the protei ....The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the proteins and hormones which regulate the way breast cells multiply. One protein which normally regulates the division of breast cells is IGFBP-3. We have found that in some breast cancer cells, IGFBP-3 is no longer able to inhibit cell division, and this may lead to tumour growth and invasion of other tissues. We are interested in finding out how IGFBP-3 normally controls breast cell proliferation, and why some breast cancers are resistant to IGFBP-3. To do this, we will use normal breast cells in culture to examine how IGFBP-3 interacts with other cellular factors to prevent cell division. We will then look at whether the breast cancer cells have changed so that they are no longer able to recognise IGFBP-3 as an inhibitory protein. This may be because of changes in the way IGFBP-3 binds to the breast cancer cell, or because of changes in the way it interacts with other proteins in the cell. Because IGFBP-3 is made by normal and breast cancer cells, we will also study whether the IGFBP-3 being made by breast cancer cells is normal, or if it changed in some way that makes it inactive. By understanding why some breast cancers are not inhibited by IGFBP-3, we will be able to design new and better methods of preventing, detecting and treating the growth of all breast tumours.Read moreRead less