Neurotoxin Exposure Treatment (Parkinson’s) Research: NETPR

Portfolio Overview:

The Neurotoxin Exposure Treatment (Parkinson’s) Research, NETPR, portfolio is dedicated to advancing solutions to the understanding and intervention in mechanisms underlying the development of Parkinson’s disease and Parkinsonian conditions.  Funded projects are required to address “dual use” needs of the portfolio in that developments of the portfolio are also intended to address risk factors for performance decrements in service men and women and develop solutions relevant to identification, remediation, or reversal of such risks in operational and deployment environments.  The portfolio uses an iterative, problem-solving approach in which funded projects have well-supported preliminary evidence, clear hypotheses and metrics and include specific means of validating findings.

The diagram highlights NETPR's focus on correlation of genetic and environmental impacts on cellular function and
identification of biomarkers, vulnerable populations, and cellular targets for therapeutic interventions.

Funding:

Projects are submitted for consideration for funding through the USAMRMC Broad Agency Announcement and specific solicitations.  They must meet the developing goals of the portfolio.  Current areas of interest/focus include:  epigenetic mechanisms associated with development of Parkinson’s in familial and sporadic PD; stable epigenetic modifications associated with organophosphate/ organochlorine correlated PD; dopaminergic Substantia nigral, ventral tegmental and striatal cellular mechanisms altered during local inflammatory processes; influence of non-dopaminergic neural transmission associated with development of non-motor signs in PD; PD associated imaging and molecular alterations of the hippocampus; molecular mechanisms affected by exercise in progression of PD.  Proposal request is likely to be restricted to one to two year pilot projects with upper limits (to include both direct and indirect costs) of $300,000.00 per year.

Specific requirements will be published with the request for proposals.  Investigators should examine proposal requests published at http://www.grants.gov for announcement of such requests.  Announcements will also be published on the TATRC web page when released through grants.gov.

Major Objectives:

The program is managed as a dual-use program. It advances understanding of Parkinson’s Disease (PD) progression and develops means of diagnosis, prevention, and therapeutic intervention for both dopamine and non-dopamine responsive symptoms, thereby enhancing strategies for treatment of motor and non-motor conditions that affect quality of life and performance for PD patients. For military service members, the research outcomes are leveraged to support long-term health and performance through an increased understanding of biologic mechanisms underlying potentially harmful military exposures, development of information on the safety of chemicals and drugs used in military operations, means of measuring environmental impacts on performance, and improvements in materiel design to reduce potential risks of military exposures.

Key tenets supporting portfolios advance are that alterations in any neurotransmitter system must impose compensatory alterations in other physiologic systems and that the motor aspects—the prime clinical diagnostic criteria of PD—are the result of convergent alterations, which are themselves the result of varied initiating vulnerabilities within the affected population. The inherent limitations of individual genetic inheritance, with an array of combinatorial effects consistent with requirements for biologic differentiation, provides diverse opportunities for environmental modulation and presentation of diverse dysfunctional clinical manifestations in the heterogeneous population.   The program’s focus (determination of neurode­generative mechanisms and related compensatory effects that compromise motor, autonomic and cognitive systems) clarifies why damage to these systems, which are characteristic of the disease in Parkinson’s patients, also provides information relevant for potential performance and health risks for military personnel from similar operational exposures.

As the risk factors for PD, noted in epidemiological research, include many of the hazards in operational environments (e.g., organophosphates, organochlorine compounds, head trauma, certain solvents, etc.), research in the portfolio provides a basis for developing spin-offs that enhance the safety and well being of military service members. The improved understanding of the pathnophysiology of neurodegenerative changes provides a basis for identifying associated risks of military hazards and development of preventive strategies and treatments which, in turn, suggest additional areas for research that can be exploited to clarify the natural progression of PD.

Achievements:

• Development of compounds, acting on intercellular signaling, for treatment of organophosphate exposure. Organophosphate insecticide and pesticide are a suggested risk factor for development of PD as well as a basis for models of the disease. In the military, insecticides and pesticide use is wide-spread as a means of countering vector borne diseases; and effects on acetylcholine esterase is the primary mode of action of nerve agents.  Projects in the portfolio investigate specific links between environmental exposure and risk factors for Parkinson’s disease.  Specific residual organochlorine compounds in human brain tissue have been identified that correlate with development of PD signs.


• Development of compounds to treat co-morbid conditions frequent in Parkinson’s patients (depression, anxiety disorders, executive function disorders, and sleep dysfunction). Depression and anxiety disorders can be a significant complication in militarily relevant conditions such as PTSD and executive dysfunction was a problem for many veterans following the ’91 Persian Gulf deployment. Irregularities in sleep are also a potential problem for military service personnel due to extreme operational tempo of many deployments.


• Neuropsychological domain functions are particularly relevant in both neurodegenerative conditions and for individuals suffering psychological or physiological alterations of brain function. The ANAM instrument, initiated through a joint military service program and optimized for determination of cognitive dysfunction associated with motor disorders, is demonstrating alterations in neuropsychological measures during progression of PD that correlate with alteration in dopamine transporter single photon emission computed tomography (SPECT) imaging. A subset of the ANAM library was optimized for use in the military to provide baseline and post-injury neuropsychological measures, which are imperative for development of relevant rehabilitative efforts of injured personnel.


• Projects in the portfolio demonstrated specific alterations associated with exercise in animal models that are correlated with slowing progression of Parkinson’s-like motor dysfunction and are being explored for means of delaying progression of Parkinson’s disease and to enhance the resilience of service personnel against the stress and hazards of deployment.


• Other projects optimized tests to define non-motor associated signs and are developing correlations of clustered signs as a means of identifying Parkinson’s development and progression prior to motor effects.  These findings will allow development of research strategies to improve quality of life and performance of Parkinson’s patients as well as aid development of rehabilitative therapeutic regimes for motor dysfunction and for developing strategies that support health and performance of military personnel.  Related projects in the portfolio improved neuroimaging methods and also determined molecular mechanisms in dopamine regulatory systems that influence development of dyskinesia.


• Important work in the portfolio is geared toward development of interdisciplinary studies to separate environmental and genetic impacts on disease initiation and progression and to identify peripheral markers of disease. It is hoped that such studies will permit development of pre-clinical diagnostic markers (prior to motor alterations) and a means of identifying peripheral compartment reporter molecules indicative of anatomical and, in some cases, cell-specific central nervous system alteration. Such markers could be useful in diagnosis and prognosis of disease. They might also permit correlation of molecular alterations in specific subsets of the population with clinical phenotype and thereby more clearly identify clinical case cohorts for more effective treatment and rehabilitation. Studies funded under the portfolio have identified peripheral transcript alterations that affect disease progression in PD models and that are also present in human PD patients.

• Bronstein J, Carvey P, Chen H, Cory-Slechta D, DiMonte D, Duda J, English P, Goldman S, Grate S, Hansen J, Hoppin J, Jewell S, Kamel F, Koroshetz W, Langston JW, Logroscino G, Nelson L, Ravina B, Rocca W, Ross GW, Schettler T, Schwarzschild M, Scott B, Seegal R, Singleton A, Steenland K, Tanner CM, Van Den Eeden S, Weisskopf M. Meeting report: consensus statement-Parkinson’s disease and the environment: collaborative on health and the environment and Parkinson’s Action Network (CHE PAN) conference 26-28 June 2007. Environ Health Perspect. 2009; 117: 117-21.
• Flajolet, M, Wang, ZL, Futter M, Shen W, Nuangcham­nong N, Bender J, Wallach I, Nairn AC, Surmeier DJ, Greengard P. Direct interaction of a G-Protein-Coupled receptor with a receptor tyrosine kinase results in syner­gistic ERK-mediated biological responses. Nature Neurosci. 2009; 11: 1402-1409.
• Marek K, Jennings D, Tamagnan G, Seibyl J. Biomarkers for Parkinson’s disease: tools to assess Parkinson’s disease onset and progression. Ann Neurol. 2008; 64 (Suppl 2): S111-21.
• Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P, Greengard P. Role of p11 in Cellular and Behavioral Effects of 5-HT4 Receptor Stimulation. J Neuro­sci. 2009; 29: 1937-1946.
• Yang L, Zhao K, Calingasan NY, Luo G, Szeto HH, Beal F. Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahdropyridine neurotoxicity. Antioxid Redox Signal. 2009; 11: 2095-104.
• Yu L, Shen HY, Coelho JE, Araújo IM, Huang QY, Day YJ, Rebola N, Canas PM, Rapp EK, Ferrara J, Taylor D, Müller CE, Linden J, Cunha RA, Chen JF. Adenosine A2A recep­tor antagonists exert motor and neuroprotective effects.

To learn more about Neurotoxin Exposure Treatment (Parkinson’s) Research (NETRP) or the Telemedicine & Advanced Technology Research Center (TATRC) contact us at:

E-Mail: parkinsons@tatrc.org
Phone: (301) 619-7036
Fax: (301) 619-7968