Gene-environment interaction in neurodegenerative disease. (Fellowships, Grants, & Awards.

There is provocative evidence that environmental exposures to certain neurotoxicants (heavy metals, pesticides, fungicides) may play a role in the development of neurodegenerative movement disorders such as Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). Recent research on these diseases has focused on both the underlying biological processes critical to disease manifestation for the development of new treatments and the relative roles of neurochemical and genetic factors in their etiologies. Much work, however, remains to be done to clarify these fundamental processes.

The objective of this three-year program announcement (PA) is to stimulate research on the relative roles of neurochemical and genetic factors in the causation of neurodegenerative diseases. This new initiative will selectively shift its research focus each year to emphasize a different neurodegenerative disease. In the current year, the special focus is on soliciting research on gene-environment interactions as a risk factor in ALS (a fatal disease of unknown etiology marked by the progressive degeneration of motor neurons) in order to stimulate much-needed research in this area. In succeeding years, there will be an announcement indicating a different neurodegenerative disease focus area.

Several epidemiological studies have implicated gene-environment interactions in the development of PD and ALS. Nevertheless, it is still not clear whether differences in prevalence rates or clusters of these diseases in various communities are due to the differential distribution of a hypothetical environmental toxicant or are more frequent where a familial heritable defect is more common. To date, analytic epidemiological studies have varied in case and control selection methodology and venues (e.g., clinics, population bases, different countries), partly accounting for the disparate conclusions reached by some investigators. While a good deal of research has been devoted to the influence of the environment in the susceptibility to PD, there has not been a similar effort committed to ALS.

Some progress has been made in recent years toward understanding the biological bases of ALS. A number of pathological, biochemical, and electrophysiological abnormalities are found in affected patients and are seen in postmortem nervous tissues. Markers for genes in familial ALS (FALS), both dominant and recessive, have been identified, but they represent only a portion of the possible gene loci. In 15-20% of FALS cases, there is a mutation of the copper/zinc superoxide dismutase (SOD1) gene on chromosome 21. However, the overwhelming majority of ALS patients do not have this mutation. Genetic studies of ALS linked to other chromosomes are needed, especially of those genes easily influenced by neurotoxicants.

It is significant that the first descriptions of ALS coincided with the Industrial Revolution. Therefore, it has been logical to consider whether environmental contamination associated with increased levels of industrial activity might be implicated in its pathogenesis. The possible role of occupational exposures in ALS has also been investigated. Epidemiological studies have implicated heavy metals and other environmental exposures as risk factors for ALS but as yet have not provided a clear directional lead. For example, various studies have looked at occupational exposure to lead, mercury, selenium, manganese, aluminum, and iron exposure in assessing risk factors for the disease. Calcium has also been studied because of suggestions that excitotoxicity and calcium channel antibodies may be implicated in its etiology. In addition, in some areas, agricultural workers seem to have a higher risk of developing ALS, whereas studies on exposure to industrial solvents and chemicals have brought mixed results.

No coherent picture has emerged from these studies, however, nor have many of them been correlated with genetic studies. Therefore, much remains to be learned about the mechanisms through which genetic mutations and other biological insults lead to pathology. The genetic defects identified in FALS have lead to the development of some useful animal models of the disease, but more models are needed to expand research on the abnormal biology of the affected motor neuron and nonneuronal cells, on nervous system response to endogenous and environmental toxins and toxicants, and on identification of metabolic, endocrine, and immunological abnormalities.

Additional research is also needed to understand the contribution of environmental exposure, endogenous susceptibility factors, and increasing age in the disease linkage. This will require a concurrent advancement and refinement of methodologies and sciences. Of particular significance may be those approaches that can be used across species from lower animals to humans. Such approaches permit a precise characterization in animal models of alterations arising from defined environmental exposures that can serve as a cogent guide to underlying cellular and molecular mechanisms in humans.

This initiative will seek to solicit novel approaches to understanding ALS, with emphasis on the role that gene-environment interactions may play in the above. Examples of research goals that could be pursued, especially in appropriate animal models and tissue culture, include (but are not limited to) the following:

1) development of animal models of ALS, especially nonmammalian models useful for gene-environment research;

2) development of biomarkers of exposure and disease in animal models (using metabonomics, for example);

3) research on modifier genes and environmental influences in animal models;

4) studies on the intersections and synergies between genetic susceptibilities and environmental factors, as well as strategies for identifying putative toxicants and other environmental factors involved in the etiology of ALS;

5) establishment of disease incidence and variation according to age, gender, race/ethnicity, geography, and exposure;

6) studies on potentially informative clusters (Western Pacific ALS/parkinsonism--dementia complex [PDC], Persian Gulf War veterans, Kelly Air Force Base workers, etc.);

7) studies on occupational/environmental exposures and nonoccupational exposures (evidence for the role of metals, pesticides, solvents, residential/avocational exposures, tobacco, alcohol, infectious agents);

8) research on the potential role of dietary excitotoxins in Western Pacific ALS/PDC and analogies with other disorders;

9) research on the role of dietary intake of antioxidants and minerals (copper, zinc, iron), and the association of fat and fiber intake with ALS;

10) research on factors targeting putative environmental toxicants specific to motor neurons and surrounding cells including muscle cells;

11) research on disease mechanisms on the cellular or subcellular level (oxidative stress, excitotoxicity, apoptosis) from neurotoxic exposures; and

12) evaluation of retrograde axonal transport of toxins to the spinal motor neurons and their response (access and possible uptake of toxic substances at the neuromuscular junction).

Moreover, the NIEHS would like to encourage multidisciplinary and interdisciplinary studies. What may be especially useful are collaborations with ongoing research in other motor disorder diseases that could be expanded to include ALS studies. We also encourage the use of novel animal models such as Drosophila, zebra fish and C. elegans, as well as newly available technologies. Especially useful would be collaborative pooling of resources to standardize epidemiological instruments, microarray analyses, "-omics" technologies, and other methods and materials for meaningful use among several laboratories.

This PA will primarily use the NIH Research Project Grant (R01) and Exploratory/Developmental Grant (R21) award mechanisms (though, if appropriate, competitive supplements may be considered if it is to accomplish collaborations). This PA uses just-in-time concepts. It also uses the modular as well as the nonmodular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise, follow the instructions for nonmodular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

The NIEHS intends to commit approximately $2 million in fiscal year 2004 to fund 10-15 new grants in response to this PA. An applicant may request a project period of up to five years for R01 grants and up to two years for R21 grants. Direct costs for R21 grants may not exceed $275,000. The characteristics, requirements, preparation, and review criteria for R21 applications are described at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.

Applications submitted in response to this PA will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. Complete information on this PA is located at http://grants1.nih.gov/grants/guide/pa-files/PAS-03-160.html.

Contact: Annette Kirshner, Cellular, Organs, and Systems Pathobiology Branch, Division of Extramural Research and Training, NIEHS, PO Box 12233, MD-23, Research Triangle Park, NC 27709 USA, 919-541-0488, fax: [phone], e-mail: [e-mail]. Reference: PA No. PAS-03-160