Grants & Funding Archive

2007 Grants

Team Parkinson is using its distribution to fund the following:

We are supporting 3 projects from the University of California (USC). These items will become part of shared resources between a number of labs investigating PD here at USC including those labs of Drs. Giselle Petzinger, Michael Jakowec, Brett Lund, Jon Walsh, Wendy Gilmore, Daniel Holschneider, and Ruth Wood. These investigators reflect the inter-departmental and multi-disciplinary approach we have here at USC in finding new treatment modalities for PD.

Project 1:

Inflammation has long been recognized as a component of PD but little is known about which immune cell types are found in the affected CNS, if they change over the course of the disease and if they play a solely destructive role in cell death, a beneficial role in neural repair and disease resolution, or a combination of both. By understanding the role that peripheral leukocytes play in the pathology that occurs following MPTP lesioning, we may be able to more accurately define the role of the immune system in PD. This project will address a fundamental question: Are peripheral leukocytes recruited to the CNS following injury? To accomplish this goal we will acquire a specialized strain of mice in which all the peripheral blood cells of the mouse will express either i) green fluorescent protein (GFP) which will cause the cells to be bright green. Mice will be administered the neurotoxin MPTP, to initiate PD-like features and the migration pattern of these cells monitored in tissues using immuno-histochemistry, advanced fluorescent imaging (in the live animal), and cell-sorting. Migrating cells will be analyzed for their molecular features to tell us their origin and function. These studies will allow us to determine the molecular link between the immune system, the peripheral system, and the progression of PD-like injury within the brain. This data is essential to support an application to the NIH on this important topic.

Dollars will be used to purchase mice, per diem, immunohistochemical reagents, fluorescent sorting, microscope supplies, technical support

Project 2:

A fundamental question in the analysis of changes (termed neuroplasticity) that take place in the brain in patients with PD and in animal models is the identity of cells within the basal ganglia and their phenotype. For example, within the basal ganglia there are 2 major types of projection neurons making contacts to other regions of the brain termed indirect and direct. Our ongoing studies have shown dramatic changes in the ability of cells in the injured brain (in which we use the neurotoxicant MPTP to replicate features of PD) to use dopamine differently if the animal is subjected to intensive treadmill exercise. These results are reported in a manuscript published in the Journal of Neuroscience and highlighted as a feature by the editor. To pursue fundamental questions of the molecular and physiological features of these cells we have to opportunity to obtain 3 important transgenic mouse strains that expression a unique molecular in our cells of interest such that they fluoresce green allowing us to monitor them and target them in our studies. These mice termed BAC-eGFP D1, D2, and TH are available from NIH supported services.

This will include purchase of breeding pairs from frozen embryonic stocks, breeding cost in our facility, and per diem costs.

Project 3:

In USC’s lab the MPTP-lesioned mouse model of basal ganglia injury serves as an important link to PD in the human condition. We are interested in the effects of intensive treadmill exercise in promoting motor improvement in this model with the intention that what we learn in the mouse will allow us to better understand how exercise and physical therapy altered the brain and can lead to improved symptoms in patients. One important question is the effects of exercise on the other motor features in the mouse. We have examined learning, memory and mood in our mode and show that some of these features are influenced by exercise in the injured brain. We need to know more about the normal movement of the mouse using an objective measure. For this purpose an activity monitor interfaced with computer imaging will allow analysis of movement of mice in their home environment. We can than monitor improvement of movement with our exercise intervention and identify important factors necessary for this benefit.

Project Title: The Study of molecular mechanisms responsible for the role in overcoming many of the motor deficits seen in injuries to the basal ganglia

Investigator: The Laboratories of Michael Jakowec, PhD, and Giselle Petzinger, MD., Department of Neurology, University of Southern California

The adult brain possesses a tremendous capacity to change in response to environmental cues including learning, memory, and injury. This phenomenon is termed neuroplasticity. One of the key areas of focus of research in our laboratories is to find ways by which we can guide neuroplasticity in the adult brain in order to overcome injuries to the basal ganglia, an area of the brain affected in Parkinson's disease. Our recent studies in an animal model of Parkinson's disease have shown that intensive treadmill exercise plays a critical role in overcoming many of the motor deficits seen in this model. In collaboration with a number of investigators at USC, we are studying the molecular mechanisms responsible for this observation. At this point we know that there are significant changes in how the brain handles dopamine including alterations in the pattern of expression of receptors that normally bind this important neurotransmitter. In addition, we have found that despite a severe depletion of dopamine, similar to that which may exist in Parkinson's disease, exercise is to change how the brain releases dopamine from remaining nigrostriatal terminals. This new way to handle dopamine may be one mechanism by which the brain is able to compensate for injury leading to improvement in motor function. We have also found significant alterations in other neurotransmitter systems in the injured brain with exercise, including changes in the expression of pathways that use both glutamate and serotonin, two systems that may lead to altered dopamine function in recovery.

An important need in our Parkinson's Disease Research Program is to improve our capacity to carryout critical electrophysiological studies of individual neurons within the injured basal ganglia of our models of Parkinson's disease. In close collaboration with Dr. John Walsh in the Andrus Center for Gerontology here at USC, we are carrying out such investigations. By studying single cells we are able to dissect their molecular profile and directly compare those whose recovery has been enhanced by exercise with those that have not. The addition of a new state-of-the-art camera to our existing equipment will allow us to improve the precision and impact of our studies. Under high magnification the new camera will assist us to probe deep within the basal ganglia, target individual neurons, gather their electrophysiological characteristics, and remove their sub-cellular contents for the molecular analysis of genes and proteins responsible for their altered function. Such information will reveal to us the important mechanisms responsible for exercise enhanced recovery of motor behavior within the injured brain and may help identify new therapeutic targets for the treatment of Parkinson's disease.

We would like to thank Team Parkinson for their support and the important role they play in making critical research studies in our laboratories at USC possible.

Project Title: FDDNP-PET as a Surrogate marker in Parkinson's disease
Investigator: Yvette M. Bordelon, MD, PhD, Department of Neurology, UCLA

I was recruited to the UCLA Department of Neurology as an Assistant Professor in November of 2004 after completing my fellowship in Movement Disorders with Dr. Stanley Fahn at Columbia University. I divide my time between clinical work in the Movement Disorders clinic and translational research (bringing the information gained from basic science laboratory investigation into the clinical practice and treatment of Parkinson disease and other neurologic disorders). I believe that we will see dramatic progress in clinical research in the next several years if we are allowed to pursue translational research projects now that will identify promising studies and techniques to expedite and refine the many impending clinical trials in the study of Parkinson disease. This translational research needs to keep pace with the basic science work in order to provide the scientific community and our patients with the meaningful results necessary to further identify the underlying causes of disease and guide disease-modifying treatments for disorders such as PD for which there are no known cures.

Surrogate markers are test results that can be used to measure a certain characteristic of a disease. Surrogate markers can be used to test effectiveness of particular treatments quickly and efficiently in clinical trials. Currently, there are no known surrogate markers for PD but the need to identify them cannot be overemphasized. Brain imaging holds the highest promise in this capacity as it is safe and non-invasive. A powerful imaging technique in the study of neurologic diseases is positron emission tomography (PET). UCLA has a long history in the field of PET imaging and is home to many researchers responsible for the development of novel imaging compounds and techniques. Recently, Dr. Jorge Barrio developed a new PET compound (FDDNP) that labels abnormal protein aggregates in brains of patients with Alzheimer disease. Altered protein processing and accumulation of protein aggregates is emerging as a common process in many neurologic diseases including Parkinson disease. Alpha-synuclein and other proteins aggregate into Lewy bodies in neurons in PD. A surrogate marker for this hallmark of PD would revolutionize the study of the disorder and expedite the identification of potentially curative therapies. We are now planning to conduct a pilot study using FDDNP-PET in patients with PD. If FDDNP-PET is able to identify abnormal protein accumulation in PD patients, the effects on the world of PD clinical trials would be far-reaching. We plan to use the funds contributed by Team Parkinson to obtain these FDDNP-PET scans in PD patients for the pilot study examining it as a possible surrogate marker in Parkinson disease. The data collected from this pilot study will then be used to apply for a federal grant to support a large project examining this technique further. The support from Team Parkinson is greatly appreciated and will have a significant impact on the conduction of this important line of research.

Project Title: Motor control studies at UCLA
Investigator: Dr. Allan Wu

The UCLA Motor Control Laboratory, under the direction of Dr. Allan Wu, within the Division of Movement Disorders, Department of Neurology, will research transcranial magnetic stimulation (TMS) studies in Parkinson's disease (PD) patients.

The goal of the UCLA Motor Control Laboratory is to apply motor control principles toward the assessment of movement problems in PD patients. Such principles have the potential to be objective markers of parkinsonian impairment which can then be used to characterize different stages of PD or to assess responses to therapy. The laboratory studies motor control by analyzing goal-directed actions (reaching, grasping, pointing) using a 3-dimensional motion capture system. Transcranial magnetic stimulation (TMS) now adds the ability to investigate the neural basis for these motor control principles.

TMS uses a brief magnetic field to noninvasively and painlessly stimulate the human brain. When TMS is applied over a given brain region during the planning or execution of a goal-oriented action, the resulting effects on that action provide information about the role that brain region plays in generating that particular movement. When applied over the motor cortex, TMS can evoke a muscle twitch. By monitoring this muscle twitch, we can obtain direct information about the activity of the motor output circuit when planning or executing movements. By examining differences in TMS effects between PD patients and normal subjects, we increase our understanding of the neural basis of normal motor control of voluntary movements and how this neural system is altered in Parkinson's disease.

Project Update 2009:

The Wu Laboratory studies the how noninvasive brain stimulation using repetitive magnetic stimulation (rTMS) can modulate and improve symptoms of Parkinson's disease (PD).  This field is advancing rapidly as shown by the recent Food and Drug Administration approval of rTMS as a treatment for patients with severe depression.  With support from Team Parkinson and the Parkinson Alliance, the Wu Laboratory developed a TMS infrastructure to study effects of rTMS in patients with PD.  In the last few years, the laboratory was awarded pilot funding to study short-term effects of rTMS in patients with atypical Parkinsonism (PSP and CBD).  In November 2009, the Michael J. Fox Foundation announced funding for a 3 year clinical trial of rTMS for the treatment of PD symptoms.  The $1.5 million project consists of a consortium of TMS investigators led by Dr. Pascual-Leone in Boston (Beth Israel Deaconess Medical Center-Harvard Medical School) and includes Dr Allan Wu (UCLA), Dr Hubert Fernandez (University of Florida in Gainesville), and Dr. Robert Chen (Toronto Western Research Institute).  This project is the first multicenter, sham-controlled clinical trial of rTMS in North America to determine the efficacy and duration of benefit of rTMS in improving motor and mood symptoms in PD.  Seed funding from Team Parkinson was instrumental in leveraging a relatively new TMS laboratory and investigator at UCLA to the forefront of current TMS research in PD.

Project Update:

The Wu Laboratory studies how noninvasive brain stimulation using repetitive magnetic stimulation (rTMS) can modulate and improve symptoms of Parkinson's disease (PD).  This field is advancing rapidly as shown by the recent Food and Drug Administration approval of rTMS as a treatment for patients with severe depression.  With local support from The Parkinson Alliance and Team Parkinson, the Wu Laboratory has developed a TMS infrastructure to study effects of rTMS in patients with PD.  In the last few years, the laboratory has been awarded pilot funding to study short-term effects of rTMS in patients with atypical Parkinsonism (PSP and CBD).  Dr. Wu has also collaborated with colleagues in Boston (Massachusetts), Gainesville (Florida) and Toronto (Canada) in  designing the first multicenter, sham-controlled clinical trial of  rTMS in the US and Canada to determine the efficacy and duration of  benefit of rTMS in improving motor and mood symptoms in PD.  The resulting clinical trial proposal is currently being reviewed for funding at both NIH and the Michael J Fox Foundation.

Project Title: Neuropsychiatric behaviors/compulsive behaviors in Parkinson's disease and the neuroimaging component of a large trial evaluating the effects of exercise in PD.

Principal Investigator: Dr. Jennifer S. Hui, MD with the division of Movement Disorders at the University of Southern California

Non-motor symptoms of Parkinson's disease: Mood, Cognition, and Behavioral Changes:

Although non-motor symptoms are often not well-recognized in Parkinson's disease (PD), they can be even more disruptive and disabling than the motor manifestations of the disease in up to 30% of patients. These non-motor symptoms include changes in mood, memory, cognition, and behavioral changes such as obsessions and compulsions.

Recent increased awareness of certain compulsive behaviors in PD has highlighted the potential role of medication in the manifestation of these behavioral changes. In particular, dopamine agonists have been implicated in compulsive gambling, shopping, eating and hypersexuality. These behaviors have not been studied in detail, and the risk factors for developing these behaviors are unknown.

Dr. Hui has been studying these behaviors in PD, and is developing an easily administered confidential questionnaire for the screening and detection of compulsive behaviors in PD. It is important to recognize these behaviors early on, because they can be alleviated by simple medication changes. A questionnaire will allow for earlier and confidential reporting of these symptoms, on topics which may be of a personally sensitive nature to patients. Additionally, identifying risk factors for these behaviors will lead to more appropriate, therapeutic choices.

To many PD patients, the non-motor symptoms of their disease are under-recognized, yet significantly impact quality of life. Research in this area is often overlooked and under-funded, making support for these projects more important for the comprehensive treatment of PD.

Project Title: Enhanced Recovery Through Treadmill Exercise in the Mouse Model of Parkinson’s Disease.

Investigator: The Laboratories of Michael Jakowec, PhD, and Giselle Petzinger, MD., Department of Neurology, University of Southern California

In early life our brain goes through a tremendous explosion of learning where we acquire new motor skills such as walking, running, ice-skating, and balance. Other parts of the brain also learn their selective functions including language, musical skills, vision, and problem solving. Until recently, it was assumed that our brains ability to change (a term called neuroplasticity) was permanently fixed once we reached adulthood, and that specific skills are selectively lost if their controlling regions within the brain are damaged through injury or disease. Remarkably, we are learning that the brain’s capacity for recovery from injury is far greater than previously recognized. Recent studies in a number of labs have shown that the intrinsic ability of the injured brain to repair, at any age, can be enhanced through activity-dependent processes including environmental enrichment, exercise, forced-use, and complex skills training. Not only can this approach be applied to clinical conditions like stroke but we are now learning that other phenomenon like Parkinson’s disease (PD) can in fact lead to functional improvement through neuroplasticity.

A primary focus of our lab is to better understand neuroplasticity (and repair) in models of PD. Both the mouse and nonhuman primate, when subjected to the neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which selectively destroys nigrostriatal dopaminergic neurons (the same neurons lost in PD), leads to behavioral and biochemical features similar to that seen in human PD. Remarkably, both the MPTP-lesioned mouse and nonhuman primate recover from the effects of MPTP but it takes a period of several months. Our goal is to find ways to enhance this natural recovery and by doing so identify new therapeutic modalities for the treatment of basal ganglia disorders including PD. In addition to pharmacological and molecular intervention strategies we have also found that we are able enhance motor behavior deficits in MPTP-lesioned mice subjected to an intensive treadmill exercise program. Interestingly, our studies indicate that there are remarkable changes in those genes and proteins involved in dopamine neurotransmission as well as another neurotransmitter system that uses glutamate. These results have recently been published in Fisher et al (2004) Journal of Neuroscience Research 77: 378-390. Ongoing studies in the lab are designed to better understand the molecular mechanisms underlying exercise-enhanced recovery in the basal ganglia. For example, we wish to know how precisely the dopamine and glutamate systems are altered, and can we further enhance the benefits of exercise or even block them with pharmacological treatment targeting dopamine and glutamate. In addition, we wish to explore important questions regarding age-related benefits of exercise, how long the benefits persists, and if other tests of motor behavior enhancement are also affected by treadmill exercise.

To accomplish these goals we would like to thank Team Parkinson’s for providing the addition of a new state-of-the-art rodent treadmill to our laboratory. This treadmill will allow us to run mice in an intensive exercise program, more accurately quantify behavioral measures, and allow computer integration of these measures. Understanding the mechanisms by which repair of the injured brain may be enhanced in a mouse model of PD, will provide valuable insights into the development of therapeutic treatments for PD. For example, by understanding the mechanisms responsible for exercise enhanced recovery will permit precise tailoring of exercise programs with specific clinical treatments, disease stages, and may identify new targets for drug discovery.

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