The 2009 Parkinson's Unity Walk Funds Research Grants

Through the generous support of its corporate sponsors, 100% of all donations made to the Parkinson's Unity Walk are distributed among the major U.S. Parkinson's disease foundations for Parkinson's disease research. The foundations include: (1) the American Parkinson Disease Association; (2) the National Parkinson Foundation; (3) the Parkinson's Action Network; (4) the Parkinson's Disease Foundation; (5) The Michael J. Fox Foundation for Parkinson's Research; (6) The Parkinson Alliance; and (7) The Parkinson's Institute and Clinical Center.

We are excited to share with you information about the following grants —all of which are made possible from 2009 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us.

Grants with progress reports from previous years are also available.


1. American Parkinson Disease Association is using its distribution to fund:


Project Title:
The Potential Role of Anti-Oxidant Systems in the Mechanism of DJ-1-Dependent Astrocyte-Mediated Neuroprotection.

Investigator: David A. Hinkle, MD, Ph.D., University of Pittsburgh, Dept. of Neurology, Pittsburgh, PA

Objective: The investigator is proposing to explore the role of glutathione as a potential regulator of DJ-1 dependent astrocyte-mediated neuroprotection in astrocyteneuron co-cultures from PD – revelant brain regions (cortex, ventral midbrain) using oxidative neurotoxins (rotenone, MPP+).

Background: The future development of disease-modifying strategies against Parkinon’s disease (PD) will require an improved understanding of not only the molecular mechanisms underlying the pathological process, but also the mechanisms through which the brain attempts to protect itself.  The identification and therapeutic augmentation of these latter processes in astrocytes, cells which abundantly survive in PD and which exhibit neuron-supportive and protective functions, may represent a novel and powerful approach through which PD progression could be attenuated.

Methods/Design: The investigator is planning:

1) to assess DJ-1 deficient/knock down (DJKD) replete/wild type (WT) vs. DJ-1 over –expressing (DJOX) cortical astrocytes for their relative abilities to express glutathione and glutathione pathway enzymes.

2) to assess the ability of exogenous glutathione to rescue co-cultured WT cortical neurons from the deficiency in cortical astrocyte-mediated neuroprotection caused by astrocytic DJKD, and the ability of glutathione pathway enzyme knock-down in WT and DJOX astrocytes to reduce their neuroprotective effects.

3) to explore the role of astrocytic DJ-1 in ventral midbrain astrocyte-mediated neuroprotection of co-cultured ventral midbrain dopaminergic neurons against MPP+ and rotenone.

Revelance to Parkinson’s disease: Try to achieve an understanding of the mechanisms through which the brain attempts to protect itself.

Project Title: Assessing the Pathogenic and Molecular Consequences of FOXO Regulation by Parkin

Investigator: Marc Tatar, Ph.D., Professor, Dept. of Ecology and Evolutionary Biology, Broward University, Providence, RI

Objectives: FOXO in mammals and Drosophila is a key regulator of the balance between cell survival and apoptosis.  The investigator proposes to establish how Parkin regulates FOXO, and whether FOXO is an intermediary factor that transduces Parkin dysregulation into neuropathology.

Background: Parkin is an E3 ubiquitin-protein ligase contributing to Autosomal Recessive Juvenile Parkinsonism (ARJP).  Emerging research reveals candidate pathways for Parkin in ARJP and suggests potential mechanisms in the etiology of sporadic Parkinson’s Disese (PD).  Impaired protein clearance within dopaminergic neurons may induce nigral degeneration in ARJP as well as in PD.  Parkin mutants may contribute to the process by misregulation of protein ubiquination that subsequently impairs proteosome function.

Methods/Design: The investigator aims to understand FOXO regulation and its neuronal consequences.  While much is known about AKT mediated phosphorylation of FOXO, the factors responsible for FOXO stability and degradation are unclear.  In mammals, FOXO is ubiquinated prior to degradation, but all of the responsible E3 ligases remain unknown.  It is from this context that the investigator has made a striking observation:   over expression of parkin markedly elevates levels of dFOXO protein.

Revelance to Parkinson’s disease:
This finding may be important in the context of Parkinson’s disease because FOXO of mammalian neurons is an important transcription factor regulating the cell stress and survival response.


Project Title: Co-transplantation of Human Retinal Pigment Epithelial  Cells to Prevent Immune Rejection of Human Embryonic Stem Cell Xenografts in Parkinsonian Rats

Investigator: Amanda Rowlands,Penn State College of Medicine,Hershey, PA

Objective: This proposal will examine the usefulness of human retinal pigment epithelial cells (hRPE) co-grafted with human embryonic stem cells (hES) in non-immunosuppressed 6-OHDA striatal lesioned hemiparkinsonian rats to provide functional recovery from Parkinsonism over a period of 3 months.

Backgound: Transplanting dopaminergic cells into the striatum of Parkinson patients has shown promise in experimental trials.  However, most dopaminergic transplants including newly defined hES have the disadvantage to requiring continuous systemic immunosuppression for successful engraftment.  Systemic immunosuppression comes with the risk of opportunistic infections and medication induced side effects.  hRPE are the exception to this requirement as they have been successfully transplanted into the striatum of non-immunosuppressed parkinsonian animals and in patients with Parkinson’s disease (PD) with no evidence of a deleterious host immune response.  Preliminary studies suggest that hRPE cell transplants are immune protected from host inflammatory cells via the secretion of immunosuppressive substances from the grafted hRPE cells and that they protect cografts of hES cells for up to 3 weeks from immune rejection.

Methods/Design: Five groups of rats will receive the following treatments:
Group 1.  hRPE mixed with hES cells attached to microcarriers
Group 2.  hES attached to microcarriers.
Group 3.  hES without microcarriers
Group 4.  hES xenografts (nomicrocarriers) with chronic daily cyclosporine injections
Group 5.  hES xenografts attached to microcarriers with daily injections of cyclosporine.

Revelance to Parkinson’s disease:
The success of this study will provide a local source of immune suppression to support successful striatal engraftment of functional dopaminergic transplants eliminating the need and risks associated with systemic immunosuppression.


Project Title:  Identification of Proteins Interacting with GIGYF2, the Product of a Putative Parkinson’s Disease Gene.

Investigator:  Dustin Freckleton, Baylor College of Medicine, Houston, TX

Objective:  The long term goal of this project is to identify intracellular pathways of GIGYF2 protein interactions that may help to shed light on Parkinson’s disease (PD) pathogenesis.

Background:  Evidence suggests that GIGYF2 mutations are associated with PD, however, the effect of these mutations on protein function is unknown.  Therefore, in addition to studying normal protein interactions, the investigator will generate expression clones containing point mutations identified in PD patients.

Methods/Design:  In this project three main questions will be addressed.  (1)  Is GIGYF2 able to physically interact with proteins already implicated in the pathogenesis of PD?  (2)  What are all the proteins normally interacting with GIGYF2 in the brain?  (3)  What is the effect of known GIGYF2 mutations on these interactions?  First, the interaction of GIGYF2 will be tested against the protein products of known PD genes as well as the known interactors of these genes (a total of over 70 different gene products).  Second, a brain cDNA library will be screened to identify new GIGYF2 protein interactors. If it is discovered that GGIYF2 does not interact with proteins already implicated in PD pathogenesis, the identification of novel GIGYF2 interactors will begin shedding some light on possible disease mechanisms related to the function of this gene.

Revelance to Parkinson’s disease:  Using these clones, the effects of the mutation on protein interactions identified above will be tested and it will be determined if these mutations exert a gain or loss of function effect on GIGYF2 interactions.


Project Title: Elucidating Relationships between Uricemia and Clinically Relevant Outcomes in Parkinson’s Disease:  Secondary Analysis of Data from a Randomized Trial.

Investigator: Daniel A. Lieberman, Massachusetts General Hospital, charlestown, MA

Objective: Studies supporting the hypothesis that serum urate levels are predictive of Parkinson’s disease (PD) risk and progression raise the possibility that elevating serum urate might be useful to prevent and/or treat PD.  A major clinical trial is currently underway to examine the effectiveness of the urate precursor inosine as a treatment to slow the progression of PD.

Background: Parkinson’s disease is a neurodegenerative movement disorder affecting approximately one precent of individuals over 55.  Treatment with dopaminergic agents such as levodopa is usually initiated when symptoms begin to interfere with quality of life and primarily control the symptoms of the disease.  Prolonged treatment with dopaminergic agents often leads to significant, disabling side effects, such as dyskinesia.

Oxidative damage is thought to play a role in the neuronal degeneration in PD.  The purine urate is a potent antioxidant and might act as an endogenous defense against oxidative stress.  Several studies have shown that healthy individuals with higher serum urate levels within the normal range are at reduced risk for developing PD.  A prospective study has also demonstrated that a diet that increases serum urate levels is associated with a reduced risk of developing PD.  In individuals with PD, higher serum urate levels within the normal range predict slower disease progression.

Methods/Design: Data from a randomized trial will be used to examine the hypothesis that serum urate levels are predictive of treatment related dopaminergic motor complications and quality of life measures in PD patients.

Revelance to Parkinson’s disease: To establish whether an increased level of serum urate may decrease the risk of developing PD or slow its progression.


Project Title: Consolidation of Motor Skills and Sleep Homeostasis in Parkinson’s Disease

Investigator: April Pruski, Sophie Davis School of Biomedical Education, New York City, NY

Objective: Little is known about the neural mechanisms that may be responsible for  impairment in the execution of automatic routine movements.  Recent studies however,  have suggested that one of the problems in using automatic routines in Parkinson’s disease (PD) patients may be due to an impairment of motor memory consolidation.

Background: In patients with PD, the execution of automatic routines is already significantly impaired in the early stages of the disease.  This impairment, which becomes progressively more severe, exacerbates the motor symptoms characteristic of PD and adds a significant burden to the execution of daily activities and to the patient’s and caregiver’s quality of life.

Methods/Design: 
1. Determine whether patients with initial, untreated PD have a selective disruption of sleep-dependent memory consolidation.

2. Determine whether in PD patients sleep SWA homeostasis is locally impaired in the cerebral cortical regions involved in motor learning.

3. Determine whether TMS applied to cortical regions involved in motor learning restores sleep SWA and sleep-dependent memory consolidation in PD patients.

Revelance to Parkinson’s disease: It would be important to determine what is responsible for this selective impairment of memory consolidation.

2. National Parkinson Foundation is using its distribution to fund the following:

Project Title:  NPF Quality Improvement Research Initiative

Investigator(s):

Jay Nutt, MD, Medical Director, NPF Center of Excellence at Oregon Health Sciences University.

Andrew Siderowf, MD, MSCE, Fellow at the University of Pennsylvania Institute on Aging and Medical Director of the University of Pennsylvania Parkinson’s Disease and Movement Disorders NPF Center of Excellence.

Project Description:  NPF, in partnership with 43 top medical centers (NPF's Centers of Excellence), has launched the first data-driven quality improvement research initiative to systematically improve care for every patient diagnosed with Parkinson’s disease. With a goal of tracking every patient seen in every NPF Center of Excellence (35,000-50,000 patients worldwide), this research initiative will generate the largest outcomes database in Parkinson’s disease.  Our ultimate aim is to create and share models of excellent care, so that every Parkinson’s patient receives the most effective treatment options available, whether they are seen by a specialist at a NPF Center of Excellence, a general neurologist or their primary care physician.  Financial support from the Unity Walk will support the initial pilot test of NPF's Quality Improvement Research Initiative, which involves collection and analysis of 600 patient records to be completed by January 2010.

3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.

PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.

4. Parkinson’s Disease Foundation is using its distribution to fund the following:

Project Title: Mechanism of FADD recruitment and activation in mutant LRRK2-induced neurodegeneration

Investigator: Hardy Rideout, Ph.D.

Project Description:  The most common genetic mutations leading to PD occur in a gene called LRRK2.  The LRRK2 gene is responsible for a protein that plays a role in signaling cells to die.  We have shown that, in neuron cells cultured in the laboratory, the LRRK2 protein must form a complex with another protein, called FADD, in order to induce cell death.  We also know that LRRK2 proteins commonly link together in two-molecule chains, and longer chains are formed when LRRK2 is mutated.  We propose that the formation of chains longer than two proteins is a critical step in the molecular pathway to cell death.  Our project aims to determine how long the chains must be for them to associate more frequently with FADD, and to discover whether this association can be blocked.  We also will examine brain tissue from people whose PD was due to LRRK2 mutations in order to better understand the connection between LRRK2 and FADD.


Project Title: The contribution of dopaminergic system in pathological gambling in Parkinson’s disease

Investigator: Antonio Strafella, M.D., Ph.D.

Project Description:  The motor symptoms of Parkinson’s disease result from a loss of the chemical messenger dopamine in certain areas of the brain.  Drug therapies to relieve motor symptoms generally work by increasing dopamine levels, but these therapies can have side effects.  In the last five years, researchers and physicians have become more aware of people with Parkinson’s developing impulse control disorders, including compulsive gambling, after beginning dopaminergic medication.  This may happen because dopamine is involved not only in how the brain controls movement, but also in its reward system.  This study uses brain scans with positron emission tomography (PET) of people with PD to characterize abnormalities in dopamine levels in two brain areas, the striatum and the prefrontal cortex, comparing people who have developed pathological gambling with those who have not.  Newly available PET tracers used to assess dopamine levels make it possible to assess dopaminergic dysfunction more accurately and comprehensively than ever before.

5. The Michael J. Fox Foundation for Parkinson's Research is using its distribution to fund the following:

PD Online Research  is an efficient Web-based platform for research professionals across the globe to engage daily on key research hurdles and breaking scientific findings.  This virtual workplace has a simple goal:  enable quicker knowledge turns and therefore faster progress toward transformative therapies.

6. The Parkinson Alliance is using its distribution to fund the following:

Project Title: Creating dopaminergic neurons with authentic Parkinson's disease - A new path to drug discovery and understanding mechanisms of neurodegeneration

Investigator: Dr. J. William Langston, Founder, CEO, and Scientific Director of the Parkinson's Institute.

Objective: The goal of this study is to derive induced stem cell lines (known as human-induced pluripotent stem cells or hiPSCs) from skin biopsies or hair taken from adult patients with Parkinson's disease (PD).  More specifically, we wish to derive hiPSCs from patients with parkinsonism due to genetic causes, including the LRRK 2 G2019S and alpha-synuclein triplication mutations. We will then use established technologies to differentiate these cells into dopamine neurons, one of the main neuronal populations that degenerate in PD.  This work will also include collaborations with academic medical centers as well as industry.

Hypothesis to be tested:  The underlying hypothesis of this proposal is that these "re-born" dopaminergic neurons that started out as skin or hair cells from adult patients with PD will recapitulate one or more of key molecular aspects of neural degeneration associated with PD in a tissue culture dish (“PD in a dish”).  We believe that this is likely since these cells will have been obtained from patients with parkinsonism of a known cause and that cause will have been carried with the hiPSCs in the form a known mutation in their DNA. 

Significance:
These proposed studies have the potential to provide an entirely new tool for investigating disease mechanisms of PD.   Furthermore, these "parkinsonian cells" could provide a transformative way to screen large number of drugs to see if they can prevent or even reverse the disease process.  The power of this approach is that it could, for the first time, provide authentic Parkinson's disease cells that are not a "best guess" model, but neuronal populations with authentic disease.  This is important because the results would be directly relevant to humans with the disease.  It is worth noting that we already have a large number of potentially “neuroprotective” drugs ready for screening. 

Deliverables/Milestones: 
The specific milestones for this project, which we estimate will take one year to 18 months, are as follows:

1.  Obtain appropriate human subjects approvals, including IRB approval for skin biopsies, and SCRO approval for derivation of iPS cells.
2.  Recruitment of 15 PD patients and controls for biopsy and establishment of fibroblast cultures.
3.  Reprogramming of fibroblasts for induced pluripotent cells (iPSCs).
4.  Characterization of ~150 iPSC clones for pluripotency and karyotype.
5.  Directed differentiation of iPSCs into dopaminergic neurons.

While this is a very ambitious set of deliverables, but we believe that they are achievable within the timeframe proposed for this research project.

Project Title:  Novel, small-molecule inhibitors of  a-synuclein assembly and toxicity for disease-modifying therapy of Parkinson's disease.

Investigator:  Dr. Gal Bitan

Project Description:  The generous gift of The Parkinson Alliance and Team Parkinson will support exciting research in the Bitan Laboratory geared towards development of disease-modifying therapy for Parkinson's disease (PD). Current treatment of PD focuses on compensation for dopamine deficiency, predominantly by using L-dopa. Though this kind of treatment is successful in alleviating major symptoms, such as tremor, it does not address “non-dopaminergic” symptoms, including falling and freezing, which affect 80-90% of patients with PD and 100% of patients with early-onset PD, or dementia which afflicts ~30% of patients with PD. These non-dopaminergic symptoms are major causes of mortality and morbidity in PD. In addition, treatment with L-dopa causes complications such as “off-time” and dyskinesia (involuntary movement). To address these unmet needs, disease-modifying, rather than symptomatic, therapy is needed. We have discovered a new experimental drug that disarms what most researchers believe to be real culprit causing PD - toxic aggregates of a protein called alpha-synuclein. These toxic aggregates are the main component of Lewy bodies, the hallmark pathologic lesion in the brain of patients with PD. The new drug inhibits the formation of these toxic aggregates and thereby prevents the initial processes that lead to development of PD. Through collaboration with Dr. Bronstein's group, the new drug was found to block the toxic effect of alpha-synuclein aggregates in cultured cells and zebra fish. The fish, which without the drug are severely deformed and die within a few days, appear healthy and normal by simple addition of the drug to the water in which they swim. Related experiments in mice show that the drug can get into the brain and remove toxic protein aggregates.

With the help of The Parkinson Alliance and Team Parkinson, we will develop this promising research in pre-clinical studies in transgenic mice in collaboration with Dr. Chesselet. Specifically, we will use mice engineered to overexpress human alpha-synuclein. The mice develop alpha-synuclein aggregates in the brain and show motor deficits already at 2 months of age. We will conduct experiments to optimize dose and treatment duration examining the effect of the drug on clearance of alpha-synuclein aggregates in the brain and on the motor abilities of the mice. In addition, we will conduct pharmacological studies to determine the optimal route of administration of the drug. We expect that these pre-clinical experiments will lead to FDA approval of Investigational New Drug (IND) status for our lead compound, facilitate initiation of clinical trials, and hopefully result in effective treatment and cure for PD.

 

Project Title:  Is there abnormal network activity in the motor cortex of 6-OHDA lesioned mice.

Investigator:  Dr. Carlos Portera, M.D., PhD

Project Description:  The current treatments for Parkinson disease (PD) offer some symptomatic relief, but often at the cost of serious side effects, including dyskinesias. The introduction of deep brain stimulation (DBS) in the treatment of PD two decades ago has arguably been the most effective treatment strategy since the discovery of levodopa. Understanding the exact mechanisms of how DBS helps PD patients will help improve this therapeutic strategy. A recent study using the 6-hydroxydopamine (6-OHDA) rodent model of PD (Gradinaru et al., 2009) suggests that DBS may help by reducing the activity of the subthalamic nucleus (STN) through its effects on the firing of neurons in motor cortex, which is the part of the brain that controls movement. This raises the possibility that neurons in the motor cortex of PD patients fire less than normal, leading to an overactive STN that produces some of the symptoms of PD. I propose to test the hypothesis that neurons are hypoactive in the motor cortex of mice that had been rendered parkinsonian by injection of the neurotoxin 6-OHDA into the substantia nigra. Specifically, I intend to examine the spontaneous activity of neurons in the motor cortex of mice before and after administering 6-OHDA. We will use the cutting-edge technique of two-photon calcium imaging to record the activity of large numbers of cortical neurons non-invasively.

These experiments will shed light into the mechanisms of circuit dysfunction in PD and may lead to improved treatments for this devastating disorder.

7. The Parkinson’s Institute and Clinical Center is using its distribution to fund the following:

Project Title:  Epidemiologic Studies of PD Etiology

Investigator:  Tanner CM, Goldman SM, Langston JW

Objective:  The goal of this study is to further investigate the hypothesis that Parkinson’s disease is a complex disorder with both genetic and environmental determinants

Background:  The cause of Parkinson’s disease is not known.  Our work indicates that no single factor causes Parkinson’s disease.  Instead, combinations of risk factors and genetic makeup determine whether an individual develops Parkinson’s disease or not. Our recent work found that specific environmental factors only increase Parkinson’s disease risk in those carrying certain genetic variants.  This effect was very large for some factors, with up to an 11-fold increased risk of Parkinson’s disease.  The goal of this research project is to expand on this ongoing work, focusing on the interplay between inherited (genetic) and acquired (environmental) factors to identify the causes of Parkinson’s disease.

Methods/Design:  We will conduct secondary analyses on the combined effects of genes and environment, taking advantage of extensive work in several large epidemiologic studies. We will focus our work in three study populations of nearly 2000 individuals.  Subjects have been identified by movement disorders experts across the U.S. and Canada.  One population is comprised of over 200 pairs of twins where one twin has Parkinson’s and one doesn’t.  Detailed lifelong information on environmental risk factors and DNA has been collected. DNA has been tested for over 1500 variations in 120 genes thought to play a role in Parkinson’s disease. We will take advantage of these populations to investigate the following hypotheses: 1) The risk of Parkinson’s disease is higher with exposure to occupational chemicals and specific pesticides, and 2) In individuals with variants of genes encoding proteins involved in the metabolism of these compounds, the effect of these exposures will be increased or decreased, in accordance with the metabolic effect of the specific variant.

Relevance to Parkinson’s disease:  Interplay between genetic and environmental risk factors has long been proposed as the cause of most Parkinson’s disease, however very few studies have ever investigated this in any detail.  This project will take advantage of a rich resource of environmental and genetic information in very large study populations.  The existing data in these populations provides the opportunity to investigate these complex effects on the cause of Parkinson’s disease, focusing on common exposures that could be easily translated into a preventive intervention.


 

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