Understanding How A Compromised Fetal Environment Reduces Nephron Endowment
Funder
National Health and Medical Research Council
Funding Amount
$736,901.00
Summary
The Grant will investigate how maternal diabetes and low protein diet affects the normal development of the fetal kidney with a focus on understanding how the number of nephrons in the organ are determined.
The kidneys of infants born preterm continue to develop after birth. However, preterm infants are exposed to high oxygen levels which may impact on ongoing development. In a rodent model of oxygen exposure, the blood vessels of the kidney and the numbers of stem cells will be assessed; additionally, further stem cells will be administered in order to try and prevent any impairment. It is expected that the findings of this study will help to explain the effects of preterm birth on the kidney.
The prevalence of maternal obesity is alarmingly high in Australia and the western world. However, there is little understanding of how obesity of the mother affects the development of the kidney of the fetus and, in turn, how this affects the risk of these offspring developing cardiovascular and renal disease in adulthood. I hope to address the gaps in this knowledge in my studies. This information is critical in order to develop appropriate health care to those born to obese mothers.
The Effects Of Pre-term Birth On The Baboon And Human Neonatal Kidney
Funder
National Health and Medical Research Council
Funding Amount
$349,248.00
Summary
LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of neph ....LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of nephrons. We have shown that the baboon is an excellent model of kidney development in humans. Like humans, we can prematurely deliver baboons and maintain them in a neonatal intensive care unit after birth. In this model, we have evidence to suggest that the formation of the the nephrons within the kidneys of the pre-term infants is impaired and we predict that this leads to impaired kidney function after birth and to susceptibility for renal disease in adulthood. In this study, we will examine kidney function in preterm baboon and human babies and also undertake studies in autopsied kidneys from baboon and human pre-term infants. We will determine whether the number and the cellular structure of the nephrons is affected by preterm delivery and if so, whether kidney function is affected. By comprehensively examining the medical records of the mother and babies, we also aim to identify factors in the care of the mother prior to birth, or of the baby after birth which may link to impaired nephron formation and kidney dysfunction in the baby. We will also determine whether administration of retinoic acid to the baboon preterm baby soon after birth can stimulate the formation of nephrons. The findings of this study will provide important new insights into the mechanisms of kidne failure in preterm babies and will identify potential strategies to prevent nephron loss and enhance nephron formation in preterm infants, which will in turn have long-term implications to kidney health.Read moreRead less
Reprogramming The Renal Epithelium To Reinitiate Nephrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$636,199.00
Summary
It has been shown that a mature cell type can be reprogrammed to a different type of cell in vivo via the introduction of genes critical during an earlier stage of organ development. In this way, new beta-islet cells in the pancreas can be made. In this study, we will use our understanding of kidney development to redirect the cells of the kidney tubules to dedifferentiate and form new nephrons. This may ultimately result in a regenerative strategy to treat chronic renal disease.
Modelling The Regulation Of Nephron Number By The Renal Stem Cell Niche.
Funder
National Health and Medical Research Council
Funding Amount
$715,935.00
Summary
Chronic kidney disease is a growing burden to the health system. The long term health of your kidneys is influenced by the number of functional units, nephrons, present in each kidney, a feature that is determined before birth. If we could influence this number, we may be able to reduce the risk of kidney disease in later life for at risk populations, including the Aboriginal community. This study will investigate the stem cells that form the nephrons, how the process occurs and how it can be in ....Chronic kidney disease is a growing burden to the health system. The long term health of your kidneys is influenced by the number of functional units, nephrons, present in each kidney, a feature that is determined before birth. If we could influence this number, we may be able to reduce the risk of kidney disease in later life for at risk populations, including the Aboriginal community. This study will investigate the stem cells that form the nephrons, how the process occurs and how it can be influenced.Read moreRead less
Genomic And Proteomic Dissection Of The Molecular Basis Of Kidney Development.
Funder
National Health and Medical Research Council
Funding Amount
$454,582.00
Summary
The number of nephrons present in the human adult kidney can vary by threefold. This is likely to be due to slight variations in the rate of nephron formation during development. Evidence is mounting that a reduced number of nephrons can predispose to renal failure later in life in response to stresses such as hypertension or substance abuse. 80,000 new cases of end stage renal failure occur each year in the US, with 25% of these related to hypertension and therefore possibly linked to a low nep ....The number of nephrons present in the human adult kidney can vary by threefold. This is likely to be due to slight variations in the rate of nephron formation during development. Evidence is mounting that a reduced number of nephrons can predispose to renal failure later in life in response to stresses such as hypertension or substance abuse. 80,000 new cases of end stage renal failure occur each year in the US, with 25% of these related to hypertension and therefore possibly linked to a low nephron number. While it is known that the kidney arises through a series of reciprocal inductive events between the metanephric mesenchyme and the ureteric bud, a better understanding of the molecular basis of these events is needed to understand what dictates nephron endowment. The Wilms tumour suppressor protein WT1 is not only mutated in some cases of the childhood kidney cancer, Wilms tumour, but is also critical for the normal development of the metanephros, as demonstrated by knockout experiments in mice. One of the earliest genes expressed in the metanephric mesenchyme, WT1 is thought to prevent this tissue from dying before differentiation, directing it to form the kidney and, postnatally, regulating normal podocyte function. Although known to be a nuclear regulatory protein, the genes directly regulated by WT1 have not been clearly or convincingly delineated. This study aims to directly screen for changes to gene expression and protein production levels induced by WT1. To do so, an array approach unique in its use of a specific array set derived from developing kidney will be used. In concert, additional specific clone sets derived from mouse kidney prior and post the commencement of nephron formation will be constructed and analysed. As WT1 is a nuclear protein involved in splicing, this study will involve a parallel investigation at a proteomic level of changes in spliceosomal proteins in response to changes in WT1.Read moreRead less