January 7, 2022
PAR-22-093, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)
PAR-22-094, Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional)
National Institute on Aging (NIA)
Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in older adults. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive domains. AD is a heterogeneous, multifactorial disease, and a challenge in AD research is to fully understand how the multiple etiologies and age-related prodromal processes contribute to the pathophysiology of the disease.
Genome-wide association studies (GWAS) and the Alzheimer's Disease Sequencing Project (ADSP) have identified many genetic variants that contribute to the risk of late-onset AD. Determining the function of identified variants, as well as other cellular factors or pathways, that directly contribute to AD is challenginge. Moreover, many AD risk loci are in non-coding intragenic or regulatory regions of the genome, making their role in disease etiology unclear. This suggests that AD risk variants may impact DNA regulatory events, such as epigenetic and chromatin states and transcriptional activity. Direct and targeted approaches are required to identify the cell biological consequences of AD risk genomic variants and other risk or disease-modifying factors or processes to confirm their role in AD.
Human induced pluripotent stem cells (iPSCs) may hold the key to studying human AD genetic and cellular processes in relevant human brain cells. The causal linkage of age- and disease-associated genetic variants and other factors to molecular and biological phenotypes in human iPSC-derived cells may suggest new mechanistic hypotheses on disease causation and therapeutic interventions. Causal genotype-phenotype relationships in AD can be determined by genome editing, via CRISPR/Cas9 for example, to engineer isogenic human iPSC lines with and without an AD genetic variant(s) or disease modifier(s). Cell-based assays can then identify causal links of genes or proteins to cellular functions in neurons or glial cells. In addition to iPSC-derived cells, approaches using directly reprogrammed neural cells (e.g., iNeurons), which may retain an aging phenotype, offer the potential to study the impact of aging on the cell biology of AD risk and disease-modifying factors in human neural cells.
The goal of this Notice of Special Interest (NOSI) is to encourage research that assesses the function of AD genetic variants and other age- and disease-modifying factors contributing to AD using human cell reprogramming (e.g., iPSCs and iNeurons) and genomic editing approaches. The impact of aging and approaches to induce or recapitulate brain aging in these human cell models should be considered, as aging is a major risk factor for AD. Assessment of variants and other risk factors should include an unbiased, comprehensive molecular phenotyping approach, for example via genomics, transcriptomics, epigenomics, and/or proteomics. Consideration should be given to not only the variants to study, but the neural cell type and stage of maturation (i.e., aging) of the reprogrammed and edited human cells. Functional analysis (e.g., maturation, cell morphology, metabolism, electrophysiology, synaptic activity, and/or connectivity) should be considered in the overall characterization of genotype-phenotype relationships. Development of high-throughput genetic, molecular, and functional assays and 3D or organoid cell systems would be complementary and important approaches to reach the goal of this NOSI. Comprehensive functional annotation of risk variants, causality of genotype-phenotype relationships of AD gene variants and other age or disease factors, and the generation of unbiased molecular datasets that can be integrated with genomic and physiological data in human cells could be an outcome of these studies.
Areas of research interest include, but are not limited to, the following:
Human iPSCs developed under this NOSI are considered unique research resources and, as such, NIH considers the sharing of such unique research resources an important means to enhance the value of NIH-sponsored research. It is expected that iPSCs developed under this NOSI will be made readily available for research purposes to qualified individuals within the scientific community.
Application and Submission Information
This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Amanda DiBattista, Ph.D.
National Institute on Aging (NIA)