Posted 24 September 2003
Alzheimer Research Consortium
Request for Applications: Creating New Models of Alzheimer's Disease
View Press Release on 2003 grantees
Purpose of RFA
This RFA solicits novel research aimed at creating and characterizing new animal models relevant to understanding the pathogenesis and treatment of Alzheimer's disease (AD). Applications may propose improving existing models, creating novel models that recapitulate AD pathology, and/or focus on specific molecular targets relevant to AD. A multidisciplinary approach to creating and characterizing novel models is encouraged, as are proposals that focus on new techniques for creating animal models, behavioral paradigms relevant to AD, brain imaging techniques, the discovery and validation of relevant biomarkers, and characterization of naturally occurring animal models. Models developed with funding from the Alzheimer Research Consortium will be made available in an equitable fashion to both academic and corporate scientists.
The development of therapies for neurodegenerative diseases such as Alzheimer's disease represents a major challenge to researchers in academia, biotechnology, and the pharmaceutical industry. The cause of Alzheimer's disease is not known. What is known is that the great majority of cases are not caused by a single gene, but by a combination of multiple genetic and environmental factors. Decades of intense research have enabled scientists to identify key events in the progression of the disease and potential therapeutic targets. Despite these advances, however, efforts to discover drugs to treat AD have been limited. The scientific community needs better animal models of AD pathology and the underlying mechanisms of the disease to further understand the disease process and to test potential drug candidates.
The development of transgenic mouse models of Alzheimer's amyloidosis has improved our understanding of the genetics and molecular pathways of Ab-peptide production and accumulation in the central nervous system. These models have been of great value in the preclinical evaluation of anti-amyloid therapies. However, the amyloid hypothesis, which states that b-amyloid is causative to the disease and that the Ab peptide is a surrogate marker for the disease, remains to be proven. Also, current models do not recapitulate some crucial features of the disease. There is a need for alternative strategies.
Neurofibrillary tangles (NFTs) and neuronal cell/synaptic loss are markers of Alzheimer's disease that are important neuropathologically and clinically. Several groups have created and characterized transgenic mice exhibiting NFT pathology and neuronal loss. These models, expressing mutant tau or over-expressing human tau isoforms, have provided proof-of-concept that aberrations in tau result in neurodegeneration resembling that found in a number of human diseases, including Alzheimer's disease (though these mice do not recapitulate all aspects of human tauopathies). Such mice provide a model system to validate new drug targets and to test novel therapeutic strategies for Alzheimer's disease. For example, recent findings based on double transgenic mice expressing mutant tau and cyclin-dependent kinase 5 (CDK5) suggest the latter as a drug target for Alzheimer's disease. Crossing NFT-bearing mice with those over expressing b-amyloid gives rise to double transgenic mice that have increased numbers of NFTs compared with their single transgenic parent. These data support a link between b-amyloid and NFTs and suggest that further studies of the new strains may reveal the molecular and biochemical underpinnings of Ab-driven NFT formation.
Building on these successes, the Alzheimer Research Consortium now calls enthusiastically for the next generation of animal models. These models may more accurately reproduce the pathologies seen in AD, incorporate relevant risk factor genes (such as APOE4, or other possible candidates, e.g., neprilysin or insulin degrading enzyme) or focus on drug targets relevant to disease progression (e.g. kinases, phosphatases, or secretases).
This initiative is intended to recruit researchers to the creation and distribution of new animal models of neurodegeneration that will enhance discovery of novel pharmacological targets. Model organisms such as Caenorhabditis elegans, Drosophila melanogaster, or non-rodent mammals are appropriate. However, preference will be given to novel mouse or rat models (the rat has the potential to be an attractive model because of its size, pharmacokinetics, accessibility for brain imaging, and behavior).
Models should exhibit specific phenotypes related to Alzheimer neurobiology, including Alzheimer-related neuronal loss, neurofibrillary tangles, b-amyloid accumulation, and specific neurotransmitters/receptors. In addition, the ideal new models should display severe neuronal degeneration and memory deficits on several cognitive tasks relevant to Alzheimer's disease. The new models may reflect other pathogenic hypotheses, such as inflammation and oxidative stress, coupled with relevant risk factors such as APOE4. The models also may provide the opportunity to validate human biomarkers and brain imaging methods.
The expectation is that within three years, recipients of funds from the Alzheimer Research Consortium will have produced one or more novel models of Alzheimer's disease-leading to better understanding of the disease process and new tools for drug discovery-and that these models will be widely available in the research community.
Applications should be no more than 5 pages long. They should provide the outline of a three-year research plan, including specific benchmarks for Year 1 and descriptions of follow-up plans for Years 2 and 3. Proposals must contain a comprehensive budget for Year 1, including personnel, equipment, supplies, animal costs, indirect costs, etc., and estimated budgets for Years 2 and 3 (funding beyond Year 1 will be based on success in meeting benchmarks and resource availability). All recipient institutions must have current status as a 501(c)(3) charity. Because all models developed with Consortium funds are expected to be made available at cost to both the academic and commercial communities, proposals must be accompanied by a signed release from the applicant institution's Technology Transfer Office (see proposal instructions). The Consortium will work with grant recipients to develop plans and resources for distribution of new models.
All proposals must be submitted by 5 p.m. EST on October 27, 2003.
This RFA has been developed by the Scientific Advisory Board (SAB) of the Alzheimer Research Consortium, in conjunction with the Consortium's Board of Trustees. The SAB will review all proposals and make recommendations to the trustees for funding. In addition, the SAB will review benchmarks for all funded proposals and, at the end of the grant year, assess how well recipients have met their goals.
The Alzheimer Research Consortium, Inc. is a non-profit corporation formed to promote human health by supporting the development of new research model systems that will lead to improvements in, and accelerate the discovery of, strategies for the diagnosis, treatment and cure of Alzheimer's disease (AD); and to facilitate the distribution of such research model systems for the betterment of human health.
Members of the Consortium include both non-profit foundations and pharmaceutical companies. Total funding available in Year 1 will be between $500,000 and $750,000. The amount of funding is anticipated to increase over time as the Consortium grows. In Year 1 the Consortium anticipates making 2-3 grants to individual labs or multi-lab collaborations. These grants will be awarded by December 31, 2003. An interim report will be required by July 1, 2004, and a proposal for Year 2 by November 31, 2004.
How to Submit an Application
The Alzforum website has generously agreed to provide a web page for researchers interested in applying for Consortium funds. For more information, please see the instructions.
Scientific Advisory Board, Alzheimer Research Consortium
Crawley, Jacqueline (National Institute of Mental Health, NIH)
Davies, Peter (Albert Einstein College of Medicine)
Duff, Karen (Nathan Kline Institute/New York University)
Hyman, Brad (Harvard University)
Mucke, Lennart (University of California, San Francisco)
Price, Donald (Johns Hopkins University)
Robbins, Trevor (Cambridge University)
Schellenberg, Gerard (University of Washington)
Wyss-Coray, Tony (Stanford University)
Linder, Carol, ex officio (The Jackson Laboratory)