Use Of Peptides From Phage Display Libraries To Probe The Function Of AMA-1 And Other Malaria Surface Proteins
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is cu ....Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is currently one of the leading asexual stage vaccine candidates. While antibodies to AMA-1 prevents malaria invasion, little is known about the role of the antigen in the invasion process. The aim of this proposal is to investigate the molecular interactions that makes AMA-1 an important player in the invasion process. We propose to map the regions of AMA-1 responsible for binding a set of peptides which we have isolated from random peptide libraries. Since these peptides inhibit the invasion of parasites into red blood cells, regions of AMA1- that bind these peptides will be of functional significance. A further outcome will be the identification of peptide residues essential for the inhibition of invasion followed by in vitro evolution of these peptides to improve their binding and inhibitory properties. A molecular description of how AMA1 binding peptides prevent parasite invasion of host erythrocytes will improve our understanding of the invasion process, and aid in improving vaccines based on AMA-1. Furthermore, this peptide-AMA-1 interaction will be assessed as a possible target for the development of novel anti-malarial therapies. Using random peptide libraries we have selected peptides that specifically bind to other merozoite surface proteins thought to be involved in merozoite invasion of erythrocytes. The ability of these peptides to inhibit merozoite invasion will be examined and characterised as described above.Read moreRead less
Molecular Characterization Of Unique Recognition Sites On The Surface Of Human Spermatozoa
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Developing an understanding of the molecular mechanisms that regulate human sperm function is central to the clinical management of male infertility, attempts to develop novel forms of male contraception and strategies for the introduction of transgenes into the male germ line. Defective sperm function is the largest single defined cause of human infertility. Despite the prevalence of this condition we have no idea how most cases of male infertility arise nor, in a vast majority of patients, do ....Developing an understanding of the molecular mechanisms that regulate human sperm function is central to the clinical management of male infertility, attempts to develop novel forms of male contraception and strategies for the introduction of transgenes into the male germ line. Defective sperm function is the largest single defined cause of human infertility. Despite the prevalence of this condition we have no idea how most cases of male infertility arise nor, in a vast majority of patients, do we understand which particular aspect of sperm biochemistry is defective. As a consequence we have not been able to develop sensitive biochemical diagnostic tests for the infertile male nor do we have any rational methods of treatment that address the cause of this condition. Similarly no new methods of male fertility regulation have been introduced since vasectomy despite the major advances that have been made in the field of female contraception over the same period of time. Clearly if we are to develop sensitive methods for the diagnosis of defective sperm function, introduce protocols for the treatment and prevention of male infertility and discover novel approaches to male contraception, we must first understand the cellular mechanisms that enable these highly specialized cells to perform their unique function. In this study we shall focus on one of the most important attributes of sperm function the capacity of these cells to recognize the egg. Once the biochemical basis of this fundamental recognition process is understood, it should pave the way for the development of clinical applications that target this signaling system with implications for a range of disciplines including reproductive toxicology, occupational medicine, family planning, infertility and biotechnology.Read moreRead less
Monoclonal antibodies, such as the cancer therapeutic Pembrolizumab, have revolutionised the treatment of cancer and many inflammatory conditions. With over $100 billion in sales in 2018, they also underpin a growing biotech industry. We have developed a highly specific, high affinity therapeutic antibody candidate, and demonstrated efficacy in animal models of malignancy. This project will advance and develop this monoclonal, allowing us to initiate clinical studies in patients.
Structure-function Relationships Of Rye Grass Pollen Allergens And Preparation Of Hypoallergenic Mutants For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$223,928.00
Summary
Grass pollen is an important cause of allergy (eg. hayfever, allergic asthma) world-wide affecting up to 30% of the population. In Australia, rye grass pollen is a clinically significant health problem costing $83-160 million per annum. At present, the main treatment of seasonal allergy is by pharmacotherapy with the use of crude extracts in specific immunotherapy which often causes large and annoying local skin reactions and may even cause anaphylaxis. Moreover, the use of crude extracts in dia ....Grass pollen is an important cause of allergy (eg. hayfever, allergic asthma) world-wide affecting up to 30% of the population. In Australia, rye grass pollen is a clinically significant health problem costing $83-160 million per annum. At present, the main treatment of seasonal allergy is by pharmacotherapy with the use of crude extracts in specific immunotherapy which often causes large and annoying local skin reactions and may even cause anaphylaxis. Moreover, the use of crude extracts in diagnosis of allergy among some atopic individuals may be inaccurate or ineffective. In the last eight years of my research, I have contributed significantly to the identification, characterisation and molecular cloning of grass pollen allergens. In this proposal, I aim to evaluate recombinant rye grass pollen allergens as standardised and more effective diagnostic reagents and, through the identification and better understanding of the allergenic segments of these proteins, to prepare recombinant mutants of the same proteins which are no londer allergenic. Avaliability of such non-allergenic protein reagents will provide safer immunotherapy in the future. Moreover, since the biolgical role, function and structure of such allergens in the grass pollen still remain largely unknown, I will aim to investigate this with the clinically significant allergens of rye grass pollen. Determination of biological function and structure of such allergens will allow their importance for the pollen-plant to be determined and, since function may be relevant to sensitisation of suceptible individuals to these allergens, these findings will stimulate the development of novel concepts in allergen prevention and therapy.Read moreRead less
Monoclonal antibodies, such as the breast cancer therapeutic Herceptin, have revolutionised the treatment of cancer and inflammatory conditions. Will over $30 billion sales in 2011, they have also spawned a growing biotech industry. We have a generated a highly specific monoclonal antibody, which has shown efficacy in models of disease. This project will further advance and develop this monoclonal, allowing us to initiate clinical studies in patients.
Development Of Stable Human Antibody Phage Display Libraries
Funder
National Health and Medical Research Council
Funding Amount
$539,644.00
Summary
Antibodies are blockbuster therapeutics for the treatment of cancer and inflammation. Unfortunately, they often display limited stability which greatly hinders development and production. This project focuses on the construction of large libraries of stable antibodies, thereby streamlining the development of new therapeutics.