Generation Of Human Intestinal Stem Cells By Direct Reprogramming
Funder
National Health and Medical Research Council
Funding Amount
$630,391.00
Summary
Intestinal stem cells (ISCs) can give rise to mini guts in vitro with exciting applications for drug screening and cell based regenerative medicine. However, currently the establishment of mini gut cultures requires an invasive procedure. By taking advantage of a revolutionary new predictive algorithm (Mogrify) we will generate ISC directly from somatic and pluripotent cell sources.
The intestinal lining is continuously renewed by specialised cells called intestinal stem cells. Stem cells throughout the body are regulated by nearby connective tissues. But, the identity of these supportive cells in the gut are unknown. We test whether a discrete population of connective tissue cells in the gut support intestinal stem cells. This project will identify new cellular therapies and targets to promote intestinal repair and manage intestinal cancer.
Sugars and non-caloric sweeteners are detected in the gut via a common sensor, which may control sugar uptake into the blood. We showed this sensor was defective in type 2 diabetic patients, which could worsen their disease. We will test if high intake of non-caloric sweeteners worsens gut control of blood glucose in healthy volunteers, and if a blocker of this sensor improves control in patients. Deep testing of this sensor will then be used to identify new drugs for managing type 2 diabetes.
ATP Release From Gastrointestinal Epithelium: A Potential Target For The Treatment Of Slow Transient Constipation
Funder
National Health and Medical Research Council
Funding Amount
$317,775.00
Summary
Slow transit constipation (STC) is a severe condition of the colon, almost exclusively affecting reproductive age women with no effective treatment. We recently found an association between STC and defects in connexin proteins in the large intestine. We aim to reveal the role of connexins and female hormones in the maintenance of normal intestinal function and their involvement in STC. The study will provide completely new perspectives in the understanding of the functional bowel disorders.
Determining The Role Of DOCK8 In CD4+ T And B Cell Differentiation And Its Implications On Autosomal Recessive Hyper IgE Syndrome (AR-HIES)
Funder
National Health and Medical Research Council
Funding Amount
$512,600.00
Summary
Autosomal recessive hyper IgE (AR-HIES) syndrome due to mutations in DOCK8 is a rare primary immunodeficiency whereby patients present with susceptibility to severe and recurrent viral infections as well as an increased risk of developing cancer, severe food and environmental allergies, and atopic disease characterised by hyper IgE and extreme eosinophilia. This grant will investigate how abnormal DOCK8 function in CD4+ T cells and B cells contributes to disease pathogenesis in AR-HIES patients.
Mechanisms And Targets Of Antibody-complement Interactions That Neutralize Malaria
Funder
National Health and Medical Research Council
Funding Amount
$647,977.00
Summary
Our project aims to identify immune mechanisms that neutralize malaria from the moment of inoculation by a mosquito, before infection can become established to prevent the development of malaria disease. Furthermore, we will discover specific targets of protective immune responses. We expect this project will provide major new advances in our knowledge of human immunity to P. falciparum malaria, one of the world’s most significant causes of mortality and morbidity, and we will use this knowledge
Development Of Techniques To Expand Enteric Neural Crest-stem/progenitor Cells And To Administer Them To The Human Neonatal Colon For Repair Of The Enteric Nervous System Deficiciency In Hirschsprung Disease.
Funder
National Health and Medical Research Council
Funding Amount
$664,820.00
Summary
Gastrointestinal tract function is controlled by nerves in the intestine. These are missing in a small segment of the colon in the serious birth defect Hirschsprung disease. Current treatment is surgical removal of the affected colon segment, but instead, it may be possible to use nerve stem cells to provide some functional recovery. In particular, we are facing two practical questions: How can we produce enough nerve stem cells? and: How can these nerve stem cells be emplaced in the colon wall?
Neurogenic Diarrhoea: Lessons From Cholera Toxin And Related Bacterial Exotoxins
Funder
National Health and Medical Research Council
Funding Amount
$543,818.00
Summary
Many bacteria that cause diarrhoea act via the gut’s own nervous system to massively increase the transport of water and salt into the lumen of the intestine. In this project we will investigate mechanisms that lead to this over-excitation of the gut’s nervous system to test the idea that this is due to a change in the properties of the final nerve cells in the normal pathway that controls water transport. This will identify novel sites for drug treatments of diarrhoea.
An Investigation Into The Molecular Basis Of MAIT Cell Recognition Of Vitamin B Based Metabolites
Funder
National Health and Medical Research Council
Funding Amount
$883,762.00
Summary
Mucosal associated invariant T cells (MAIT cells) are an abundant T-cell population in humans, that is found mostly in the gastrointestinal mucosa. We have recently shown that MAIT cells can be activated by metabolites of vitamin B. This proposal will investigate how the MAIT cells "see" vitamin B metabolites. This research will pave the way for novel therapeutics that can modulate MAIT cell activity.
The Interplay Between Viperin, Peroxisomes And The Cellular Innate Antiviral Response
Funder
National Health and Medical Research Council
Funding Amount
$556,127.00
Summary
Infection with a virus initiates a cellular antiviral response that attempts to limit viral replication, however how this response is regulated is not well understood. In this proposal we will investigate a cellular protein (viperin) that can regulate this process by interaction with peroxisomes to amplify the antiviral response. This work will provide possible targets for therapeutic manipulation of the innate immune response that will be applicable to a wide range of viral infections.