Mbalaviele Lab

Gabriel Mbalaviele, PhD

Gabriel Mbalaviele, PhD

Research focus

The research in my lab is based on the emerging concept that low grade inflammation is a component of skeletal homeostasis whereas uncontrolled excessive inflammation causes bone damage.  Specifically, we focus on the role of auto-inflammation in skeletal pathophysiology by targeting cells of the innate immune system.

Current projects

Role of inflammasomes in osteoclast biology

NOD-like receptors (NLRs) associate with caspase-1 directly or indirectly via the adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), to form intracellular protein complexes, called inflammasomes.  The inflammasomes are active predominantly in myeloid cells where they mediate the maturation of cytokines of the interleukin-1 (IL-1) family, and cause a form of cell death, named pyroptosis.  Our work focuses on the NLR family, pyrin domain-containing 3 (NLRP3), one of the most studied inflammasomes, owing to the plethora of its activators.  Indeed, NLRP3 is activated by numerous pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs) or gain-of function mutations, which cause auto-inflammatory disorders known as cryopyrinopathies.  We also target the NLR family, CARD containing 4 (NLRC4) inflammasome whose activating-mutations in humans cause macrophage-activation syndrome.

Our own results indicate that genetic or pharmacologic manipulation (by means of bone-derived DAMPs) of the inflammasomes in myeloid cells cause profound skeletal effects in mice, due to abnormal osteoclastogenesis.  We are currently elucidating the molecular mechanism by which genetic or DAMP-activation of the inflammasomes causes skeletal manifestations.  We expect that findings from this project will position the inflammasomes as potential therapeutic targets for diseases of bone loss.

Transcriptional regulation of osteoclast differentiation by PARP1

Poly(ADP-ribose) polymerases (PARPs) catalyze the formation of poly-ADP-ribose (PAR) polymers by transferring several ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) onto acceptor proteins, a post-translational modification termed PARylation.  PARP1 is the prominent member of this family involved in DNA repair, cell proliferation, metabolism and survival.  Emerging evidence suggests that PARP1 also plays an important role in cell fate determination through regulation of transcription. Indeed, it can activate or repress transcription via protein-protein interactions, PARylate transcription factors, thereby affecting their transcriptional activity or affect gene expression through epigenetic regulation.  PARP1 can also influence chromatin modification by PARylating histones at residues that are also regulated by methylation or acetylation.

We find that PARP1 gain-of-function mutation in myeloid cells hinders osteoclast differentiation whereas loss-of-function promotes this process.  We are currently studying the mechanism of action of PARP1 on osteoclast development with the anticipation that breakthroughs in this research will enable the development of new therapeutics for the treatment of osteoclast-mediated aberrant osteolysis.

 

Publicatons

View all published research on PubMed »

Lab members

Current

  • Yael Alippe, PhD, Post-doctoral Research Associate
  • Dustin Kress, Pre-med Student
  • Chun Wang, PhD, Staff Scientist
  • Jianqiu Xiao, PhD, Post-doctoral Research Associate
  • Tong Yang, MD Candidate, Visiting Student

Previous

  • Sheri L. Bonar, MS, Senior Research Technician
  • Manisha Dixit, PhD, Post-doctoral Research Associate
  • Jacqueline Kading, BS, Research Technician II
  • Chao Qu, PhD, Post-doctoral Research Associate
  • Sheree Speckman, PhD, Post-doctoral Research Associate
  • Jeong Sung Yeop, BS, Research Technician II

Join this lab

To inquire about available positions for DBBS graduate students or postdocs, please contact Dr. Mbalaviele by email at gmbalaviele@wustl.edu.

Mbalaviele Lab, from left to right; back row: Gabriel Mbalaviele, Dustin Kress, Tong Yang; front row: Chun Wang, Jianqiu Xiao, Yael Alippe.