Adult Stem Cell Transplantation Therapy In Parkinsonian Rat
Funder
National Health and Medical Research Council
Funding Amount
$526,517.00
Summary
Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson' ....Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson's disease is incurable but the symptoms can be controlled with medications that replace the lost dopamine. Medications become less effective as the disease progresses and there is need for new therapies. Worldwide the hunt is on to discover new cell transplantation therapies to replace the dopamine in the brain and to prevent degeneration of the still surviving dopamine cells. Although embryonic stem cells might be useful for such therapies, they raise the risk of tumour formation from the transplanted cells. This aim of this proposal is to test, in parkinsonian rat, a therapy in which adult stem cells from the patient are transplanted into their own brain to provide a new source of dopamine. We have discovered a new and unique source of adult stem cells, the sense organ of smell in the nose. Small samples can be taken through the nose and we can grow these adult stem cells from people of all ages, including people with Parkinson's disease. As adult stem cells they avoid the ethical issues associated with embryonic stem cell transplantation and as cells from the same patient, they are not rejected by the immune system. This is being tested in principle by a world-first clinical trial in which we are taking another cell type from the nose, growing it in the lab, and transplanting into the injured spinal cord in a search for a cure for paraplegia. This project takes the first steps to developing a new treatment for Parkinson's disease using a patient's own adult stem cells.Read moreRead less
New Dopaminergic Neurons In The Parkinson's Disease Striatum: Establishment Of Phenotype, Function And Origin.
Funder
National Health and Medical Research Council
Funding Amount
$156,493.00
Summary
Parkinson s disease is usually associated with loss of dopamine cells that send nerves from the substantia nigra to the striatum. However, we have found large numbers of apparently new dopaminergic cells in post mortem tissue from the striatum of 10 patients with Parkinson s disease but not in 5 age-matched controls. Our aims are firstly to determine whether these cells are indeed dopaminergic neurons by establishing their neurochemical and morphological profiles. This is required to determine w ....Parkinson s disease is usually associated with loss of dopamine cells that send nerves from the substantia nigra to the striatum. However, we have found large numbers of apparently new dopaminergic cells in post mortem tissue from the striatum of 10 patients with Parkinson s disease but not in 5 age-matched controls. Our aims are firstly to determine whether these cells are indeed dopaminergic neurons by establishing their neurochemical and morphological profiles. This is required to determine whether these apparently dopaminergic cells do indeed produce the neurotransmitter dopamine and to determine to what class of neuron they belong. The latter is important to establish whether they act locally in the striatum or extend their influence over a larger area of the brain. Secondly we shall assess their function in human and rat tissue. We shall determine whether their number is related to the severity of damage in Parkinson s disease, or whether L-DOPA therapy, which most patients receive, plays any role in their appearance. These experiments will lay the ground work to allow us to determine whether these cells are beneficial or harmful. Lastly, we shall determine where these cells come from. We shall determine whether they have always been present but have taken on a new function, or whether they are in fact new cells which have been born recently. This knowledge is essential if we are to be able to change their numbers to improve treatment of Parkinson s disease. We estimate that there are up to 66,000 of these dopaminergic cells in each striatum of patients with Parkinson s disease. This is enough to have a significant impact on the manifestation of the disease. These cells might be beneficial, allowing the brain to maintain essential functions for longer or they might be harmful playing a role in either development of Parkinson s disease itself or the harmful side effects of L-DOPA therapy.Read moreRead less
The Role Of Heterochromatin In Regulating Cellular Proliferation And Development
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the ....Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit (euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell type is organised into a unique and dynamic chromatin pattern and this pattern determines the gene expression profile. This investigation will show that the critical cellular mechanism that determines the chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin. Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin formation controls the rate of cellular proliferation. This information will provide new insights into how gene expression profiles are established at precise times in early development, and offer a new strategy to inhibit the proliferation of cancer cells.Read moreRead less
Impaired Bone Remodelling Leads To Failure Of Orthopaedic Prostheses
Funder
National Health and Medical Research Council
Funding Amount
$515,917.00
Summary
The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active in ....The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%, meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties fail. It is becoming more common for young, active individuals to receive joint replacement surgery to improve their quality of life. This, combined with increasing life expectancy, and the known higher rate of failure of joint replacements in younger patients, means that the morbidity of a failed replacement, and the mobidity and associated mortality of revision surgery, will become an increasingly important health issue, with a major impact upon health budgets. The overwhelming majority of hip and knee prostheses have metal or ceramic on polyethylene bearing surfaces. It is now apparent that most implants fail due to bone loss around them leading to loosening, and evidence is accumulating that polyethylene wear particles are a major contributing factor to this process. It is therefore vital that we obtain better understanding of the causes of implant failure in order to extend the life of these implants and this project is designed to do so.Read moreRead less
The Function Of An Essential Histone Variant During Early Development.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capable of blocking gene expression therefore one important function of chromati ....Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capable of blocking gene expression therefore one important function of chromatin is to prevent unwanted gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer could result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or disrupt, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialised forms of these histones (variants). It is thought that these histone variants could specifically expose certain genes and thereby turn them on. Once the correct protein is made in sufficient amounts the histone variants could be rapidly exchanged for the normal histones to shut off the gene. Employing a new approach, we will study one of these histone variants to discover the role it plays in turning genes on at precise times in early development during the formation of different specialised cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
Differential Regulation Of Human Tyrosine Hydroxylase Isoforms And The Development Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$325,591.00
Summary
Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than othe ....Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.Read moreRead less