NIH – Development and Validation of Advanced Mammalian Models for Alzheimer’s Disease-Related Dementias (ADRD) (R61/R33 Clinical Trial Not Allowed)

Alzheimer’sdisease-related dementias (ADRD) are a group of progressive, neurodegenerative disorders with mid- to late-life onset, including Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), frontotemporal degeneration (FTD) and mixed etiology dementias (MED). Although the ADRD each have characteristic behavioral, cognitive and pathological features, symptomatic overlap and multiple neuropathological processes are common for these disorders, leading to substantial diagnostic challenges. Moreover, knowledge about the molecular pathobiology underlying these disorders remains incomplete, generating a major barrier to therapy development.

A variety of animal models, including mammalian models, have been developed to advance research into the molecular and cellular mechanisms of ADRD, to identify therapeutic targets, and to test therapeutic candidates. While existing ADRD animal models have enabled progress toward each of these objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular, cellular, behavioral and cognitive pathology observed in typical dementias, including ADRD. In addition, existing animal models typically lack consideration of common comorbidities (e.g., cardiac disease, metabolic disorders including type II diabetes, sleep disorders, gastrointestinal dysfunction, immune dysfunction) as well as the influence of external exposures or insults (e.g., head trauma). Expert recommendations from the LBD, VCID, and FTD sessions at the Alzheimer’s Disease Related Dementias Summits (convened by the NINDS in 2013 and 2016 in response to the National Alzheimer’s Project Act), all emphasized the critical need for the development of new multi-dimensional animal models that successfully replicate combinations of co-occurring pathological characteristics of human dementias.

Purpose

The goal of this FOA is to encourage research to develop and comprehensively characterize multi-dimensional mammalian models designed to exhibit a broad range of features characteristic of human ADRD. Proposed models should show a mid- to late-life onset consistent with the disorder being modeled, multiple age-dependent and brain region-specific neuropathological processes and the associated behavioral, cognitive and/or physiological abnormalities. Although the proposed animal model is not required to reproduce every characteristic of the targeted ADRD, all models should be designed to develop more than one type of pathology (e.g., abnormal protein deposition, cerebrovascular disease, cerebral inflammation) that progresses with aging. Models that demonstrate a cognitive or behavioral phenotype reminiscent of the human ADRD are strongly encouraged. Genetic manipulations in the animal model should mimic the genetic component of the human disorder being modeled as closely as possible. The development of ADRD animal models with multiple genetic or other manipulations to model mixed brain pathologies and comorbidities is encouraged. For each proposed mammalian model, a relevant suite of phenotypes that inform human ADRD disease progression and mechanisms should be characterized across the full life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood.

This FOA strongly encourages development of mammalian models that exhibit cerebral disease with one or more of the following brain pathologies: (i) Lewy bodies, (ii) tau pathology and/or beta-amyloid plaques, (iii) TDP-43-proteinopathy, (iv) vascular including cerebrovascular and cardiovascular, or (v) other relevant brain pathologies. Characterization of systemic disease and chronic comorbidities is in scope and is encouraged as scientifically relevant to the model.

Appropriate applications will propose to develop animal models that 1) are in mammalian organisms; 2) exhibit mid- to late-life onset with progression and 3) have, at a minimum, two brain pathologies, or, one brain pathology plus a common chronic comorbidity (e.g., cardiac disease, metabolic disorders including type II diabetes, sleep disorders, gastrointestinal dysfunction, immune dysfunction). Applications that do not meet these criteria will not be supported.

Examples of activities that are not appropriate for this FOA include, but are not limited to:

  • Any research involving human subjects
  • Research to develop, characterize and validate animal modelsin non-mammalian species
  • Research to characterize and validate previously developed mammalian models of ADRD

Phased Award Activities

The development, characterization and validation of mammalian animal models of human disease is inherently a multi-step process that includes initial feasibility testing followed bydetailed characterization and validation. Therefore, this funding opportunity will use a biphasic, milestone-driven R61/R33 mechanism. The R61 phase will support the development of the ADRD mammalian model and feasibility testing through initial characterization of salient phenotypes in an animal cohort of appropriate size. The R33 phase will support in-depth longitudinal characterization of neuropathology, physiology, genetics, behavior, cognition, and other relevant attributes that are essential components of the targeted ADRD as well as complete validation studies. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. The milestones should be clearly defined, quantifiable, and scientifically justified to allow the Program Director(s)/Principal Investigator(s) and Program Official assess progressinthe R61 phase.

Examples of activities for the R61 Phase include, but are not limited to:

  • Development of the mammalian model;applicants choosing to further develop an existing mammalian animal model (e.g., of a systemic, comorbid disease) into an ADRD model should fully characterize the model for any existing neuropathology (e.g., ischemic stroke, vascular disease, tau deposition)
  • Preliminary characterization of salient phenotypes in an animal cohort of appropriate size
  • Scale-up for characterization and validation studies in the R33 phase (breeding, aging, etc.)

Examples of milestones for transition from the R61 to the R33 phase:

  • Demonstration that the new animal model can be bred to sufficient cohort sizes to enable appropriately powered characterization and validation studies
  • Demonstration that the new mammalian animal model can survive to an age range that is relevant to the disease onset of the ADRD being modeled
  • Provision of preliminary evidence of age-related, human ADRD-relevant phenotypes in an appropriately sized cohort of animals and in both sexes
  • Provision of preliminary evidence that the new mammalian animal model is superior to existing and already available models for ADRD, or addresses a specific gap in modeling these disorders, and thus a rationale for transition to the R33 phase

Examples for activities in the R33 Phase include, but are not limited to:

  • Comprehensive, rigorous and appropriately powered characterization of relevant molecular, cellular, pathological, physiological, behavioral and/or cognitive phenotypes that inform human ADRD disease progression and mechanisms across the full life span or, for longer-living mammalian models, throughout the disease-relevant stages of adulthood and in both sexes
  • Rigorous and appropriately powered validation studies such as replication in a different animal cohort at the same site or at a different site, demonstration of similar responsiveness to pharmacological treatments, etc.

Additional Considerations: Applicants are strongly encouraged to contact Scientific/Research staff to discuss potential research projects prior to submitting an application.

NHLBI Interest Statement

The NHLBI supports research to understand the normal biological function of the heart, lung, blood and sleep (HLBS), as well as the pathobiological mechanisms important to the onset and progression of HLBS diseases. The NHLBI has shared interest with NINDS in VCID and is interested in applications proposing new VCID mammalian models that leverage known cardiovascular diseases and risk factors for dementia, either alone or in the presence of other AD/ADRD pathology and comorbidities such as sleep, blood, lung disorders, head trauma, and corresponding changes in the blood brain barrier. In addition, NHLBI is also interested in further characterization, optimization and repurposing of existing cerebrovascular and cardiovascular mammalian models to be used for VCID research.

Additional specific topics of interest include but are not limited to the following:

  • Determine the temporal sequence and causality of known cardiovascular risk factors for dementia in models of VCID, including the underlying biological processes, vascular changes, and the resulting brain pathologies and changes in cognitive function.
  • Characterize changes in cerebral vasculature and cognitive function in potential animal models for VCID that were originally designed as models of cardiovascular diseases and have well-documented phenotypes in peripheral vasculature and other organs, such as models for hypertension, small vessel disease, atherosclerosis, atrial fibrillation, and heart failure.
  • Characterize HLBS changes preceding cognitive impairment in animal models of VCID that have well-established phenotypes in the brain.

Deadlines:  February 14, 2019 (letters of intent); March 14, 2019 (full proposals)

URL:  https://grants.nih.gov/grants/guide/pa-files/PAR-19-167.html