SiRNA Induced Transcriptional Silencing Of HIV-1: Elucidating The Mechanisms And Exploring Options For Delivery
Funder
National Health and Medical Research Council
Funding Amount
$512,631.00
Summary
Current drug therapy for HIV is for life We have discovered a set of molecules that will turn off the ability of HIV to reproduce itself. These molecules are from a new family of RNA molecules . A single dose of these molecules suppress the ability of the virus to reproduce itself for more than a month. Further we have found ways of extending this supressive ability to greater than one year. These studies will tell us how these molecules work and how they might be effectively administered.
In the past few years, an expanding number of small RNAs (ribonucleic acids) have been discovered that play a critical part in regulating multiple steps involved in the development of human tumors. One of the genes critically implicated in the development several human cancers (including breast, lung, brain, prostate and colon) is the epidermal growth factor receptor (EGFR). As a consequence, the EGFR is a key target for new biological therapies designed to reduce signaling through the EGFR path ....In the past few years, an expanding number of small RNAs (ribonucleic acids) have been discovered that play a critical part in regulating multiple steps involved in the development of human tumors. One of the genes critically implicated in the development several human cancers (including breast, lung, brain, prostate and colon) is the epidermal growth factor receptor (EGFR). As a consequence, the EGFR is a key target for new biological therapies designed to reduce signaling through the EGFR pathway resulting in reduced growth. Using a computer-based algorithm, we have recently discovered that one of these small RNAs (or microRNAs) is a master regulator of EGFR levels in human breast and lung cancer. When we add the specific microRNA to cancer cells with excess EGFRs and low levels of microRNA, we can abolish EGFR expression almost completely, associated with cell death. From our studies, it appears that the level of this microRNA in tissues relates inversely to the level of EGFR. As the major site of expression of this microRNA is in the brain, we were intrigued to demonstrate that the normally high level of the microRNA is lost in brain cancers (or gliomas) which are associated with high levels of EGFR. Thus, the loss of microRNA may enable the tumor to develop, suggesting that the microRNA may act as a tumor-suppressor . In this project, we will investigate the functional role of this microRNA in a range of human tumors, determine if it can work synergistically with other new biological therapies targeting the EGFR signaling pathway, identify some of its binding partners and determine the levels of EGFR and the microRNA prospectively in a cohort of gliomas. These studies will determine the functional role of the microRNA and form the foundation for further studies to consider strategies to deliver the microRNA for therapeutics.Read moreRead less
Intestinal Adaptation Following Massive Small Intestinal Resection: Mechanisms And Management
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Short bowel syndrome (SBS) remains a major clinical problem in paediatric and adult clinical practice. The Department of Gastroenterology and Clinical Nutrition at the Royal Children's Hospital has gained recognition as a national centre of excellence for the management of infants and children with SBS and intestinal failure. Due to the significant personal and heath-care burden related to SBS there has been an urgent need to improve understanding about the process of intestinal adaptation follo ....Short bowel syndrome (SBS) remains a major clinical problem in paediatric and adult clinical practice. The Department of Gastroenterology and Clinical Nutrition at the Royal Children's Hospital has gained recognition as a national centre of excellence for the management of infants and children with SBS and intestinal failure. Due to the significant personal and heath-care burden related to SBS there has been an urgent need to improve understanding about the process of intestinal adaptation following massive small bowel resection (MSBR) in order to develop new treatments aimed at improving clinical outcome for patients with SBS. Over the past 5 years we have developed a preclinical model for the study of intestinal adaptation in infants using the juvenile pig. Our recent studies in this model have revealed that elemental formula is inferior to whole protein formula suggesting that the current clinical recommendations need urgent re-evaluation. Using the preclinical model in this proposal, we aim to define the mechanisms underlying the adaptive response and evaluate novel therapies aimed at enhancing adaptation following MSBR. Supplementation of enteral feeds with bovine colostrum isolate resulted in normal growth in the preclinical model despite MSBR. In this proposal we plan to advance this observation for the first time to human clinical trials in infants with SBS. Even small gains in enteral tolerance during the early post-operative period may have a significant impact on morbidity and mortality of children with SBS due to parenteral-nutrition related liver disease and gut-related sepsis. This research proposal provides a unique link between studies aimed at providing the scientific basis for understanding the mechanisms of intestinal adaptation using an established preclinical model and translating the results of these studies onto human trials, taking advantage of the clinical expertise available in the management of children with SBS.Read moreRead less
Regulation Of Intestinal Stem Cells And Intestinal Growth
Funder
National Health and Medical Research Council
Funding Amount
$419,018.00
Summary
How the small intestine grows is important for preterm babies and those with short bowel syndrome. This study investigates the mechanisms of growth in the normal situation and in animal model of short bowel syndrome. It investigates particular growth pathways that regulate growth and particularly that of intestinal stem cells.