The genetic causes of kidney disease - a new disorder discovered
Prof. Robert Kleta and his research group at UCL Medical School and Great Ormond Street Hospital for Sick Children, London, have a particular interest and research expertise in the genetic causes of kidney diseases, especially those rarer inherited diseases that affect the function of the kidney epithelial (tubular) cells and which often first come to light in early childhood. Such studies require powerful computers with special software, because many thousands of gene sequence variations from the affected families have to be analysed and compared with the data held in the large genome databases that are now available. Funding provided by the Trust and the Grocer’s Charity have made it possible for simultaneous sequencing of very large quantities of DNA, screening up to 50 genes of interest without difficulty. Prof. Kleta has already used the technology to complete a collaborative study which reported a new finding of major importance where a combination of basic and clinical research across disciplines has identified a mutation on a single gene - KCNJ10 - inherited by certain children that can cause them each to suffer from several different and very debilitating diseases that were not previously thought to be linked. It has been named the EAST syndrome, due to the presence in these children of Epilepsy, Ataxia, Sensineural deafness and renal Tubulopathy. The significance of this finding has been recognised internationally and the results have been published in a leading American medical journal.
Prostate cancer stem cells and their role in the disease process
Dr. Hide Yamamoto, working with Prof. John Masters, is studying stem cells from the prostate gland which are thought be responsible for prostate cancer development, with the aim of developing a novel stem cell based approach to the treatment of prostate cancer. The Trust has provided running costs for the project.
Stem cells are important basic cells which replenish and replace old and dying cells with new ones, and ensure that a person’s organs are in good working order. Evidence from different cancers, however, has shown that they also contain their own rare ‘cancer stem cells’ which replenish the cancer and cause it to continue spreading. A cancer without cancer stem cells is similar to a tree without its roots, making it shrink and become less active. The project was started by using human tissue donated by hospital patients to study the properties of normal prostate stem cells. Methods have now been developed by Dr. Yamamoto for separating the minute stems cells from others in the tissue, using both lasers and magnetic fields. He has also discovered ways to grow them for prolonged periods in a specialised laboratory environment. Following this success, the same processes will be used on cancer stem cells in order to compare the behaviour of the normal cells with those from the cancerous tissue. In the long term this will proceed to investigation of various ways to target cancer stem cells using nanotechnology and novel drugs. The results have been presented at several international conferences.
The kidney filtering system and factors influencing its function
The main purpose of the kidney is to filter the blood circulating through the body and to remove the toxic waste products of metabolism - allowing filtration and formation of urine but preventing leakage of blood cells, proteins and larger molecules. The structure in the kidney that provides this ‘sieve’ within each of the kidney nephrons is called the glomerulus. A disease such as diabetes can damage the specialised cells that comprise this complex filter and the barrier function is lost. The hallmark of such diseases is protein leak into the urine and this can indicate progressive kidney failure. Diabetes remains the commonest cause of kidney failure worldwide.
Dr. Rob Blaber, together with Dr. Jill Norman and Dr. John Connolly in the Centre for Nephrology at UCL have been studying a growth factor present in the body, known as the Vascular Endothelial Growth Factor (VEGF). This is an entity whose effects on the kidney are very complex but vitally important for the maintenance of kidney filtration function. Efforts to inhibit the action of VEGF, for example in treating cancer, or to use it as a treatment of some medical conditions by attempting to grow new blood vessels, have both resulted in kidney damage and leak of protein in the urine. The goal of this project has been to understand how VEGF operates, and the following discoveries have been made:-
The group has demonstrated the unique signalling pathways inside cells that control the effects of VEGF and have identified these pathways as potential targets for drug development to treat kidney damage.
They have successfully established the culture of glomerular cells in the laboratory and their response to VEGF. Excitingly, they have developed a means of stimulating these cells to form blood vessels in culture. This assay method is being used to examine how kidney blood vessel growth is regulated and work is underway to establish a system in which cells grow together, producing a kidney glomerulus in culture. If successful this would be the first such experiment.
Podocytes are branching cells that surround the tiny blood vessels in the kidney (capillaries) and prevent leakage of protein from the great amount of blood filtered by the kidney each day. Over recent years there has been much interest in these cells as many genetic forms of kidney disease have been found to be due to inherited defects in podocyte proteins, and damage to them is also thought to be central to kidney disease resulting from diabetes. The group has now cultured and characterised podocyte cells in the laboratory and is examining how they function.
This work has been funded by St. Peter’s Trust and the Eranda Foundation and is being presented at international nephrological meetings and prepared for publication.
Bladder disorders - a possible link between low-grade persistent urinary tract inflammation and an over-active bladder
Dr. Khasriya and Dr. Lunawat, in a group led by Prof. Malone-Lee have studied the substances released in the inflammatory processes, the chemical response to inflammation and the role of bacterial infection as a cause for the inflammatory signal in the condition known as over-active bladder. A variety of detailed tests were undertaken and led to the conclusion that bacteria capable of causing urological disorders invade the lining of the bladder wall (urothelium) and continue to exist, concealed within the cells of the tissue, causing inflammation (cystitis) even after any apparent urine infection tested by routine methods has been cleared. Although biofilm-like colonies of bacteria (biopods) were not actually found within cells in the patients in the study, the data produced from the tests pointed to undetected bacterial infection with colonisation of the cells in the bladder wall as a cause of the over active bladder. Acute/chronic cystitis was found in association with this, plus changes in the urothelium and strong symptom links to these pathologies.