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Title page for ETD etd-01222018-164000


Type of Document Dissertation
Author Tahaei, Seyedmohammad Ebrahim
Author's Email Address s.m.ebrahim.tahaei@gmail.com
URN etd-01222018-164000
Title Molecular Bases of the Reduced Osteogenic Differentiation Potential in Nf1 Deficient Osteoprogenitors
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Joey Barnett Committee Chair
Alan Brash Committee Member
Ana Carneiro Committee Member
Florent Elefteriou Committee Member
Jeffrey Davidson Committee Member
Keywords
  • RNA-Seq
  • Neurofibromatosis type 1
  • Bone marrow stroll cells
  • Differentiation
  • MAPK signaling
  • Epiregulin
Date of Defense 2018-01-18
Availability restricted
Abstract
Neurofibromatosis type 1 results from mutations in NF1, a gene that encodes Neurofibromin. This common genetic condition is associated with tibial pseudarthrosis (PA), whose etiology is unknown but thought to involve defective bone-repairing osteoprogenitors. The main objective of my thesis was to delineate the causal determinants of the poor osteogenic potential of Nf1-/- osteoprogenitors. I showed that increased Epiregulin and TGFb1 expression does not contribute

to the reduced osteogenic differentiation of Nf1-/- osteoprogenitors, and contrary to all expectations, that this phenotype is likely independent from MAPK/ERK constitutive signaling. Using a RNA-Seq approach, I identified changes in pro-inflammatory and extracellular matrix gene signatures as putative determinants of the impaired differentiation of Nf1-/- osteoprogenitors. Finally, I obtained preliminary data pointing to inhibition of RUNX2 activity upon loss of Nf1 function. These results suggest unexpected interactions between Neurofibromin and proximal cell signaling/adhesion components that impact not one but multiple downstream signaling pathways.

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