PUBLIC ABSTRACT. Degenerative brain diseases account for a huge portion of the health burden for our society. Most are largely untreatable or, at best, inadequately treated. A number of devastating human neurological diseases are caused by abnormalities of the ways in which signals are transmitted from one brain cell to another and from one part of the brain to another. One of the most important signal systems in the brain and one that is most vulnerable to inherited or acquired damage is the system that is regulated by a special class of nerve cells (neurons) that use the molecule dopamine to transmit signals to other neurons and other cells in the brain. The most common of dopamine-deficiency diseases is the familiar Parkinson’s disease that afflicts millions of people throughout the US and hundred of thousands of Californians. Unfortunately, for many reasons, the causes of the dopamine degeneration in this disease are difficult to study, partly because most cases of this disorder seem to be caused by complex interactions among a number of genes or by mixtures of genetic and environmental factors. Only a few cases are caused by identified simple defects in the genes responsible for producing or maintaining the dopamine neurons. Fortunately for an understanding the genetics of the dopamine signaling system, another disorder of dopamine function, Lesch Nyhan Disease, is caused by defects in one single gene called HPRT. The disorder is associated with severe retardation, abnormal movements and a compulsive and untreatable self-mutilation behavior and is largely untreatable. Because the disease is a direct result of abnormalities in a single, well-understood gene, it is possible to study the ways in which genetic damage can cause defects in the dopamine systems, changes that are directly responsible for the severe neurological consequences. Because the damage to the dopamine pathways produces defects of the dopamine-dependent cells themselves, we propose to study the ways in which stem cells develop into mature normal dopamine nerve cells. There are a variety of cells that have developed along the pathway from stem cells to normal nerve cells but that have not reached the stage of functioning dopamine nerve cells. We wish to determine if we can force these cells as well as the stem cells themselves to become functional dopamine neurons by treating them with a collection of more approximately 50,000 chemicals. If these studies area successful, we may be able to understand the dopamine development process more thoroughly and possibly also to prepare large numbers of normal dopamine-producing cells for eventual transplantation approaches to these devastating diseases.
BENEFIT TO CALIFORNIA Advances in modern molecular genetics are making possible new approaches to understanding the basis of normal and abnormal human biology and to improve treatment of human disease. Studies of human embryonic stem cells promise to become an important part of this new area of biomedicine, but many kinds of studies have been severely hampered in the U.S. by a restrictive national policy and inadequate funding mechanisms. Wisely, the people of California have taken steps to catalyze this field through the formation of the California Institute for regenerative Medicine (CIRM) and through the CIRM programs to support research in this area. Our studies, if successful, will contribute to an understanding of a basic process of brain function and will therefore strengthen the huge basic research effort in neurobiology at the California-based academic institutions. Furthermore, knowledge and techniques derived from this kind of study can be applied to the discovery and development of drugs that specifically affect neuron function and that potentially affect the movement, cognitive, mood, compulsive and aggressive behavioral aspects of brain disorders, all of which represent the central features of Lesch Nyhan Disease. Another potentially useful outcome with commercial implications could involve methods to produce large amounts of dopamine-producing cells for transplantation for treatment of some kinds of brain disorders and the development of similar approaches to other neurotransmitter CNS disorders. Such discoveries will constitute the basis for expanded and new pharmaceutical and biotechnology ventures in California, with the health and economic benefits that such progress carries with it.