Jada Selma

BME PhD Proposal 

Date: August 3, 2017

Time: 12:00 pm

Location: Suddath Seminar room (IBB 1128)

Advisor: Edward A. Botchwey, PhD

Thesis committee:  Manu O. Platt, PhD

                               Wilbur Lam, MD, PhD

                                Fredrik Vannberg, PhD

                                Luke Mortensen, PhD

Title: The Role of Sphingolipid Metabolism in Bone Stem Cells and Sickle Bone Disease

Abstract: Sickle cell disease (SCD) is the most common inherited blood disorder in the U.S. SCD affects approximately 100,000 people domestically and an additional 300,000 babies born globally every year. A collection of pathologies, including osteonecrosis (ON), osteoporosis (OP), and osteopenia, known as sickle bone disease (SBD) are among the most common complications of SCD, which progresses from adolescence and occurs in 50% of individuals by age 35. Transgenic sickle mouse model studies have shown that increased osteoclast activity and reduced mesenchymal stem cell (MSC) differentiation into osteoblasts contributes broadly to pathological bone remodeling in SCD, but underlying cellular and molecular mechanisms are poorly understood. Sphingosine 1-phosphate (S1P), a type of sphingolipid (SL), directs a wide array of cellular processes including, migration, cell-cell adhesion, survival, and proliferation. S1P has also been found to direct MSCs towards an osteogenic lineage and modulates their migration. Moreover, we previously showed that dysregulated sphingolipid (SL) metabolism in SCD increased production and release of cell-derived microvesicles (SS MVs), which in turn induced pro-inflammatory cytokine secretion, dysregulation of mitogen activated protein kinase (MAPK) signatures, and elevated proteolytic activity of cathepsins (cat) S and K. The overall hypothesis of this proposed research is that dysregulated sphingolipid metabolism and signaling within MSCs reduces osteogenic potential and contributes to sickle bone disease. First, we will determine if differences in sphingolipid levels between normal and sickle MSCs contribute to sickle MSCs’ decreased ability to differentiate into osteoblasts. Second, we will utilize endogenous MSC mobilization to enhance allogenic MSC survival and engraftment and subsequent bone regeneration in a SCD murine model. This work will elucidate potential therapeutic targets for ON treatment in SCD as well as improve MSC therapy for other bone disorders.