R01AG072705

Discovery of Osteoblast and Osteoclast Bone Mass Effector Genes Using Advanced Genomics

Osteoporosis is a devastating disease of bone that impacts over 10 million Americans. While the cellular basis for osteoporosis includes an imbalance in bone formation by osteoblasts and bone resorption by osteoclasts, there are relatively few validated, clinically relevant genes directly linked to osteoporosis. There is a significant need to discover new genes that influence osteoporosis pathogenesis. Discovery of new osteoporosis genes will eventually permit the field of bone and mineral biology to achieve the long-term goal of developing new therapies to both prevent and treat this debilitating disease.

The existing, long-term collaboration between the Hankenson and Grant laboratories has been focused on understanding the functional significance of genome-wide association study (GWAS) signals associated with bone mass, osteoporosis, and fracture risk. We have developed methods to use those signals to identify novel genes putatively involved in disease pathogenesis. While GWAS efforts by numerous research groups have been successful in discovering genomic variants robustly associated with bone mineral density (BMD) and fracture, GWAS only reports signals associated with a given trait and not necessarily culprit genes.

In this proposal, we utilize a computationally advanced, multi-step process that integrates genome-level data to identify novel osteoblast and osteoclast genes. This bioinformatically-driven "genome-wide variant to gene mapping" effort combines RNA-Seq, ATAC-Seq, and high-resolution chromatin conformation capture methods to implicate culprit effector genes. We have already used this approach in osteoblast lineage cells, and 30% of osteoporosis-associated GWAS signals were shown to have direct physical contact with genes in these cells, totaling 86 putative target genes. Several of these targets (e.g., EPDR1, ING3) have already had extensive functional follow-up. However, many more need functional follow-up, and there are still 70% of osteoporosis-associated GWAS loci that remain unresolved.

Importantly, our initial work focused only on discovering osteoblast-associated genes, and thus genes that play a role in osteoclasts were not revealed. Furthermore, our published work to date has only focused on one time-point during the osteoblast differentiation process, thus genes that play roles at later points in cell differentiation have not been discovered. This comprehensive application will functionalize GWAS findings and, in doing so, reveal novel genes involved in regulating bone formation and resorption.

Our established pipeline from gene discovery to gene validation has been robustly tested, and thus far, although our sampling has been small, we have had a 100% hit rate for validating putative effector genes. Thus, it is our hypothesis that we can uncover many more BMD effector genes by conducting high-resolution "genome-wide variant to gene mapping" in osteoclasts and osteoblasts. The relevance of genes will be validated using both in vitro and in vivo approaches in mouse models. Upon completion, we will provide the bone community with new targets to pursue for understanding mechanism.

Regents Of The University Of Michigan

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]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 04/30/26 to 04/30/27 and the total obligations have increased 411% from $655,493 to $3,348,887.