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.
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.
Effects Of Intestinal Inflammation On Functioning Of Enteric Neurons: From Animal Models To Humans
Funder
National Health and Medical Research Council
Funding Amount
$345,206.00
Summary
Crohn’s disease and ulcerative colitis, two debilitating conditions known as Inflammatory Bowel Disease (IBD), affect more than 61,000 Australians. There is no cure for IBD. All gut functions are controlled by enteric neurons in the gut wall. Inflammation causes damage and death of these neurons leading to gut dysfunctions. This is the first study defining the classes of human enteric neurons affected by inflammation. This study will test several potential new targets for the treatment of IBD.
Advanced Imaging To Define Hepatic & Intestinal Drug Disposition In Aging & Liver Diseases
Funder
National Health and Medical Research Council
Funding Amount
$762,123.00
Summary
Aged people and liver disease patients have impaired drug absorption and elimination functions. Their response to drugs varies widely when given drug dosage regimens recommended for normal patients. This project will explore the possibility of using in vivo imaging techniques to define the gut and liver function and their response to administered drugs. This grant will help the selection of appropriate drugs and doses for aged people and patients with liver diseases, i.e. personalised medicine.
Building An Intestine: Manipulating Regeneration Of The Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
Diseases, infections and pathologies are common clinical problems of the intestinal lining in both infants and adults. Individuals with these conditions can experience nutritional problems and severe cases result in death. The intestinal lining is generated from a small population of stem cells. In this study we use of a mouse model where the stem cells are marked and will examine what factors regulate stem cells in the intestine with the aim of facilitating intestinal tissue regeneration.
The Mechanisms Through Which Opiates Cause Gastrointestinal Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$410,594.00
Summary
Opiates are the mainstay analgesics for severe pain. However, their use in pain relief can be greatly limited due to gut-related side-effects. These include chronic constipation, which is mediated through actions on neurons in the intestine. In this proposal we will examine the role of key proteins, known as beta arrestins, in the generation of opiate-induced constipation. Knowledge derived from this study will facilitate the development of analgesics with fewer gastrointestinal side-effects.