U01AG072577

Circular RNAs and their Interactions with RNA-Binding Proteins to Modulate AD-Related Neuropathology - Summary

New variants, especially in non-coding regions, are expected to be discovered through the ongoing AD Sequencing Project (ADSP). This proposal will investigate circular RNAs (circRNAs) and RNA binding proteins (RBPs) that regulate or are regulated by these circRNAs.

Recent genomic studies have discovered thousands of circRNAs produced from both protein-coding genes and non-coding regions of the genome via a process known as back-splicing. circRNAs are more enriched in neuronal tissues and are often derived from genes specific for neuronal and synaptic function. The discovery of these circRNAs demands a coordinated investigation of RBPs that interact with the circRNAs.

Mutations in and dysfunction of RBPs are known to be major mechanisms contributing to the pathophysiology in frontotemporal dementia, ALS, and AD. However, the contributions of the circRNA:RBP network to these disease mechanisms are largely unknown. The novel biology of circRNAs opens an entirely new window into mechanisms of neurodegeneration in ADRD.

circRNAs could contribute to neurodegeneration by acting as sponges that sequester miRNA/RBPs away from normal mRNA targets, altering splicing or expression. RBPs also regulate circRNA production by binding to the flanking intronic sequences of circRNAs, which contain many conserved binding sites of splicing factors/RBPs. Thus, sequestration of RBPs in protein aggregates could cause dysfunctional regulation of circRNAs.

The history of genomics indicates that the discovery of each new nucleotide species expands our understanding of disease mechanisms. The discovery of circRNA presents a major unexplored avenue of RNA metabolism that demands investigation. We hypothesize that changes in the levels of circRNAs contribute to the pathophysiology of ADRD, and that the discovery of key circRNAs or circRNA-RBP interactions in aging human brains could uncover novel biomarkers, disease mechanisms, or therapeutic targets.

In this proposal, by leveraging large public and our own RNA-seq data (rRNA-depleted), we will apply several methods to detect and characterize AD-related circRNAs from multiple human brain regions and integrate them with ADSP genetic findings (Aim 1). In Aim 2, aside from discovering AD-related RBPs from human brain RNA-seq, proteomics, and ADSP WES/WGS data, we will leverage the ENCODE CLIP-seq data for RBP binding to identify putative RBP-circRNA interactions with AD, i.e. AD-related functional RNA elements. Finally, in Aim 3, we will select the top 10% of the circRNAs (~200) and RBPs (~150) for further high-throughput functional evaluation with a novel, powerful 3D human organoid model of ADRD, termed ASTAD, that exhibits the full range of tau pathology and neurodegeneration.

We anticipate that our integrative analyses of ADSP genetics, circRNA, mRNA, RBP, and the high-throughput ASTAD functional screen readouts can help generate testable hypotheses for future molecular mechanisms experimental design.

Trustees Of Boston University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Boston, Massachusetts 021182642 United States

Single Zip Code

Alzheimers Disease Sequencing Project Functional Genomics Consortium (U01 Clinical Trial Not Allowed) (RFA-AG-21-006)

Amendment Since initial award the total obligations have increased 388% from $773,463 to $3,774,499.