The purpose of the Lewy Body Dementia Center Without Walls (CWOW) program is ultimately to understand how toxic species of alpha-synuclein and amyloid-beta produce the clinical pathology characteristic of Lewy Body Dementia. This FOA invites applications that will systematically and comprehensively characterize alpha-synuclein and amyloid-beta subspecies found in human LBD post-mortem brain tissue, identify toxic subspecies and potential mechanisms of toxicity, and characterize any interactions between the proteins that may contribute to increased toxicity and/or explain selective vulnerabilities of cells/circuits. Given the heterogeneity of both alpha-synuclein and beta-amyloid subspecies, applicants will be expected to focus on the use of post-mortem brain tissue from subjects with LBD; human neuronal cultures/slices/organoids, and human blood/stem cells/CSF from subjects with LBD may also be used for this purpose. It is expected that a multi-site, multidisciplinary team with expertise in 1) mapping neuronal protein structure, function, and interactions at multiple levels, and 2) elucidating neurodegenerative mechanisms that are likely to be relevant to LBD, will be necessary. All centers will be expected to produce a publicly-available library of fully characterized alpha-synuclein and amyloid-beta subspecies found in LBD.
The National Alzheimer’s Project Act (NAPA) was passed in 2011 with a primary research goal aimed at finding a way “to prevent and effectively treat Alzheimer’s by 2025.” Since then, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held multiple research summits to assess the needs and opportunities relevant to this goal for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. In particular, the NINDS has convened expert panels in 2013 (https://www.ninds.nih.gov/About-NINDS/Strategic-Plans-Evaluations/Strategic-Plans/Alzheimers-Disease-Related-Dementias) and again in 2016 (https://www.ninds.nih.gov/News-Events/Events-Proceedings/Events/Alzheimers-Disease-Related-Dementias-Summit-2016) that were tasked with recommending research priorities for advancing the state-of-the-science for the Lewy Body Dementias as well as other types of dementias. During both summits, panel members identified critical new research targets and tools that will be essential for understanding and developing treatments for these disorders. Panel members emphasized the need to systematically characterize disease-specific changes in LBD brain tissue so that underlying disease mechanisms could be identified and used to guide future biomarker and therapeutic approaches.
LBDs, which include Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), present clinically with the motor symptoms typical of Parkinson’s disease (PD) in addition to cognitive deficits as may be seen in Alzheimer’s disease (AD). This combined clinical picture is reflected in the neuropathology, which in LBD is characterized by the accumulation of alpha-synuclein in Lewy Bodies (as seen in PD) and amyloid-beta in amyloid plaques (as seen in AD). To a lesser extent, the tau in neurofibrillary tangles (as seen in AD) may also be seen in LBD tissue. In PD, AD, and LBD, these abnormal proteins accumulate in many of the same brain regions; however, they are also found in some regions that are relatively unique in LBD (e.g., Lewy bodies in the cortex).
The normal functions of amyloid precursor protein and alpha-synuclein are poorly understood. Both proteins are amyloidogenic and capable of aggregating into oligomers, amyloid fibrils and beta sheets; however, for both proteins, aggregates exhibit substantial heterogeneity in composition and structure. This heterogeneity makes it difficult to answer key questions about which specific subspecies are neurotoxic, which conditions promote the formation of neurotoxic subspecies, how the proteins cause neurotoxicity, and why some brain regions are more susceptible to neurotoxic aggregation than others. It may also slow the development of diagnostics (e.g., PET ligands) and treatments (e.g., pharmaceuticals), since these are typically based on a clear knowledge of target protein structure. In general, more work has been done to answer these questions for amyloid-beta aggregates than for alpha-synuclein aggregates, and almost none of this work has been done specifically in LBD. Even less is known about whether the co-occurrence of both types of abnormal aggregates, as seen in LBD, is simply coincident or is due to some common mechanism/vulnerability. Since both types of aggregates are present in patients with LBD (i.e., the same “brain tissue environment”), this disease may present a unique opportunity for comparing and defining neurotoxic aggregate subspecies, mechanisms, and selective regional vulnerabilities.
Specific Research Objectives and Requirements:
Applications to this FOA will be expected to focus on identifying and cataloging alpha-synuclein and amyloid-beta subspecies found in human LBD post-mortem brain tissue and characterizing their potential mechanisms of neurotoxicity. Human neuronal cultures/slices/organoids, and human blood/stem cells/CSF from subjects with LBD may be used in addition to post-mortem brain tissue. Each LBD CWOW application should propose an overall hypothesis to explain not only how neurotoxicity is induced by these aggregates, but how these aggregates and their mechanisms of toxicity might interact with each other and/or contribute to selective vulnerabilities of cells and circuits. All proposed projects and cores for the CWOW must collaborate seamlessly to address this overall hypothesis; applicants will be expected to clearly describe how each component synergizes with the others and justify why each is necessary to achieve the overall CWOW goal. At least 3 projects must be proposed.
Depending on the overall hypothesis of the CWOW, its component projects might seek to address one of these areas of interest (among others):
- Determining the metabolic, signaling or (epi)genetic factors that contribute to the transformation from normal to abnormal proteins in LBD.
- Delineating the unique structural/functional characteristics of abnormal alpha-synuclein and beta-amyloid in LBD compared to those in related disorders (e.g., PD, AD).
- Identifying neuronal mechanisms for processing abnormal proteins and the conditions under which these become altered, inadequate or overwhelmed in LBD.
- Elucidating differences and similarities in how alpha-synuclein and beta-amyloid are processed by neurons within the same LBD brain tissue.
- Elucidating differences and similarities in how alpha-synuclein and beta-amyloid are processed by neurons in LBD brain tissue versus brain tissue from other neurodegenerative disorders.
- Elucidating regional differences and similarities in how alpha-synuclein and beta-amyloid are processed by neurons within the same LBD brain tissue (i.e., identifying conditions predisposing to regional vulnerabilities).
- Determining mechanisms by which pathology progresses from one brain region to another in LBD.
- Examining whether toxic subspecies of alpha-synuclein and beta-amyloid interact to promote or accelerate neurotoxicity in LBD.
Since the structure of both alpha-synuclein and beta-amyloid are notably heterogeneous, applicants will be expected to focus on the use of human tissue in all projects. All CWOW applications must include a letter of collaboration/support from an existing brain tissue repository with post-mortem brain tissue from patients with LBD sufficient to support the needs of the projects. All LBD brain tissue must meet standard diagnostic criteria for DLB or PDD (e.g., DLB Consortium/McKeith criteria). The collection of new post-mortem brain tissue, blood, or CSF will be allowed if needed to support projects that propose innovative uses of fresh human tissue (e.g., human neuronal slices, human primary neuronal cultures, neuronal organoids, etc.); such projects are encouraged. If previously collected pre-mortem human blood, CSF or stem cells will be used, clear details on how the specimens were processed and stored must be provided. For any newly collected samples, applicants are encouraged to follow protocols established by the Parkinson’s Disease Biomarker Program (PDBP) or the Alzheimer’s Disease Neuroimaging Initiative (ADNI) for biospecimen collection and storage.
Centers with a primary or substantial focus on understanding alpha-synuclein or beta-amyloid in the context of neurodegenerative diseases other than LBD, or on the use/development of animal models, will be considered nonresponsive. Development of new brain banks/tissue repositories will also be considered nonresponsive. The use of non-human tissue or immortalized cell lines would only be considered acceptable if used for secondary validation and if strongly justified.
LBD CWOWs are expected to involve collaborations between multiple investigators at multiple sites in order to maximize: 1) access to cutting-edge technologies, 2) use of the highest quality resources, and 3) opportunities for innovation in research ideas and design. CWOW applications centered at a single research site will be considered nonresponsive. Given the scope of this research challenge, it is anticipated that applicants will need to assemble a world-class scientific team with expertise in a broad range of research areas, such as protein biology (structural and functional), human neuropathology, neurodegeneration, genetics/epigenetics, and any other discipline(s) considered necessary to address the center’s proposed projects. Applicants are encouraged to consider including team members with expertise from outside of the traditional neurosciences, when appropriate to the research questions proposed. The inclusion of foreign investigators/sites is appropriate if justified.
In addition to the research projects, all applications must include an administrative core that will be responsible for overseeing the progress of all projects, convening regular teleconferences and in-person meetings, and working with NINDS program officials. The administrative core will also be responsible for developing a publicly-available library of all alpha-synuclein and amyloid-beta subspecies characterized by the center. As appropriate and consistent with achieving the goals of the program, the administrative core is expected to include a plan for sharing any unused LBD brain tissue and/or biospecimens that is collected by the center. Up to two additional cores (e.g., structural biology, neuropathology, etc.) may be proposed if justified to support methods and/or resources that are integral to the overall goal(s) of the LBD CWOW and that are required by multiple (at least two) CWOW projects. Applicants are encouraged to utilize existing resources for sharing purposes (e.g., the RCSB Protein Data Bank, the NIH NeuroBioBank, the PDBP, etc.) whenever possible.
Applicants to this program who are investigators on PD or AD related NIH-supported centers (e.g., Udall Centers, AD Centers, etc.) must include a letter from the relevant center director describing how the existing center and the proposed LBD CWOW are complementary and detailing what support (resources and budgetary) will be available to the LBD CWOW.
All projects should be supported by a timeline and yearly milestones for completion. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Achievement of milestones will be evaluated by NINDS, and funding of non-competing award years will depend on milestone accomplishment. Note that these awards will be managed as cooperative agreements; therefore, projects that do not comply with terms, conditions, and established milestones of the award and of this program may be terminated early.
Applicants are strongly encouraged to consult with the NINDS Scientific/Research contact when planning an application for further guidance on program scope, goals, and developing appropriate milestones.
Deadline: January 4, 2019 (letters of intent due 30 days prior to deadline)
Filed Under: Funding Opportunities