Department of Orthopaedic Surgery

Dr. Nam Vo receives NIH R01 Grant Award

Dr. Nam Vo and the Ferguson Spine Lab have been awarded an R01 grant from the National Institutes of Health for their project "Mechanisms of Cellular Senescence Driving Intervertebral Disc Aging through Local Cell Autonomous and Systemic Non-Cell Autonomous Processes."  

Award:  $2,386,261
Funding Period:  5/15/23 - 1/31/28

Grant Abstract:

Intervertebral disc degeneration (IDD) underlies many spinal disorders resulting in debilitating back pain, disability, and tremendous economic loss.  Aging is the greatest risk factor for IDD and yet the biology of disc aging is still poorly understood.   Our prior research demonstrated that persistent DNA damage promotes senescence cells resulting in their acquisition of the senescence-associated secretory phenotype (SASP) that produces copious inflammatory and catabolic factors that promote disc matrix loss, a universal feature of disc aging and degeneration.  While these findings greatly advance our understanding of disc aging, they also raise important questions.  Does cellular senescence mainly drive disc aging locally, systemically, or both?  In other words, do senescent disc cells with tissue-destroying SASP locally drive disc aging in a cell-autonomous manner, or do senescent cells from other tissues systemically promote disc aging through the endocrine action of their SASP and signaling factors through non-cell autonomous mechanisms? Moreover, which of the two major cellular senescence pathways, p16INK4a or p21Cip1, predominantly drive the local cell-autonomous effects and the systemic non-cell autonomous effects on disc aging?  Based on our preliminary data, we hypothesize that cellular senescence drives disc aging predominantly through p16-mediated systemic cellular senescence and moderately through p21-mediated local disc cellular senescenceWe propose three specific aims to test this hypothesis using several innovative transgenic mouse strains: (1) Determine the relative contributions of local (cell autonomous) and systemic (non-cell autonomous) processes in driving disc cellular senescence and age-dependent IDD; (2) Determine the relative contributions of p21Cip1 and p16INK4a -mediated cellular senescence on age-dependent IDD; and (3) Test senolytic treatment for slowing age-dependent IDD.  Completion of the proposed studies will determine whether disc aging is driven predominantly by local or systemic processes and whether these processes are mediated primarily through the p21Cip1 or p16INK4a cellular senescence pathway.  Finally, our proposed studies will identify novel senolytic drugs for treating and slowing down age-dependent IDD.
 

Congratulations to Dr. Vo and the Ferguson Spine Lab team!