Thyroid-sympathoadrenal Regulation Of Human Brown Fat
Funder
National Health and Medical Research Council
Funding Amount
$447,141.00
Summary
This project aims to determine how hormones influence the growth and activity of brown fat in humans. Majority of fat cells in the body are white fat cells, which store fat, and cause obesity when in excess. Brown fat cells function like generators. They burn fat and release energy as heat. Humans with lots of brown fat are lean. What controls brown fat activity is currently unknown in humans. This project investigates how hormones influence brown fat activity and may shed light on the therapeut ....This project aims to determine how hormones influence the growth and activity of brown fat in humans. Majority of fat cells in the body are white fat cells, which store fat, and cause obesity when in excess. Brown fat cells function like generators. They burn fat and release energy as heat. Humans with lots of brown fat are lean. What controls brown fat activity is currently unknown in humans. This project investigates how hormones influence brown fat activity and may shed light on the therapeutic potential of brown fat in obesity treatment.Read moreRead less
Biomarkers, Related Mechanisms And Technology To Improve Diabetes Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$474,513.00
Summary
Diabetes can cause eye, kidney, heart and nerve damage. The applicant will lead human studies of treatments to prevent complications, improve blood glucose and co-ordinate care. Early outcome prediction would enable better treatment of high-risk people, monitoring of therapy, and development of new treatments. Dr Jenkins also has a network with data and samples from over 35,000 people with diabetes, preliminary data, and a team to measure markers and test new treatments in the lab.
Steroid hormones, such as estrogen and androgens, act in the body by locking onto 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 exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto 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 exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
CHAPERONES IN BREAST CANCER AND ESTROGEN RECEPTOR FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$256,573.00
Summary
Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor res ....Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to hormone. Through a novel mode of action, coumarin-based Hsp90 inhibitors disrupt Hsp90 dimerization causing receptor release and subsequent depletion. We will confirm this novel mechanism for new, high affinity Hsp90 inhibitors and determine which can best interfere with estrogen signalling, either alone or in combination with antiestrogen therapies in the treatment of hormone-dependent cancers. Our study has the potential to pin point the site of action of the immunophilins in ERa to a proline in a region critical for ligand-induced receptoractivation. We will determine the role of the immunophilins and this active-site proline residue in modulating receptor stability and function. Aberrant expression of receptor-associated immunophilins appears linked to endocrine resistance and metastasis in breast cancer. Our study will profile the expression of these chaperones in well defined breast cancer tissue microarrays, and has the potential to identify them as informative biomarkers in the treatment of the disease.Read moreRead less
Mitochondrial Sirtuins, Energy Metabolism And Insulin Action
Funder
National Health and Medical Research Council
Funding Amount
$582,925.00
Summary
Post-translational modification of lysine residues has a major influence on protein function. Many mitochondrial proteins are affected by lysine modifications and recent work has described a role for sirtuin enzymes in regulating these processes. This proposal will investigate whether targeted increases in sirtuin activity can improve mitochondrial function and insulin action in mouse models of obesity and insulin resistance.
In men, oestrogen may be important for strong bones and maintaining a healthy weight. Men with prostate cancer are given medical castration treatment to decrease testosterone, because testosterone is required for prostate cancer growth. Because oestrogen is derived from testosterone, they also have very low oestrogen levels. We want to conduct a trial in these men to find out whether giving back oestrogen will prevent bone loss and weight gain, among other health benefits.
Novel Interplay Of Oestrogen And Growth Hormone In Regulating Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$673,045.00
Summary
These studies provide insights into the mechanisms and role of oestrogen in regulating whole body and liver fat metabolism. Oestrogen-related medications that modify the action or tissue availability of oestrogen are widely used therapeutics and can predispose to obesity and fat accumulation in the liver. Whether the effect is direct or through interplay with other metabolic hormones is unknown. This proposal examines their metabolic consequences and impact on obesity and liver health.