Victor Omojola

PhD Proposal Presentation

Date: April 15th

Time: 12:00 – 2:00 pm

Bluejeans: https://bluejeans.com/538756232?src=calendarLink

Thesis Committee:

Manu O. Platt, PhD (Advisor)

Rudolph L. Gleason, PhD (Advisor)

Edward A. Botchwey, PhD

Rodney Averett, PhD

Luke Brewster, MD, PhD

Title:  Cathepsin and Thrombospondin-1-Mediated Vascular Remodeling and Altered Arterial Mechanics in Sickle Cell Disease and Peripheral Arterial Disease

Abstract:

Arterial stiffening is an underlying mechanism of cardiovascular disease (CVD) which is the leading cause of death in the world, accounting for 32.1% of deaths in 2015. Stiffening of the large arteries—peripheral arterial disease (PAD)—doubles cardiovascular mortality in older individuals. CVD may primarily affect older adults; however, in sickle cell disease, the impacts of CVD are seen in early childhood—11% of children with SCD are at risk of having an ischemic stroke before age 20. Sickle cell disease (SCD) is the most common inherited blood disorder, and is a health disparity, affecting approximately 1 in 500 African-Americans. In SCD, it has been observed that cysteine cathepsin expression is increased in the arterial wall. Other work implicates cathepsins in pathological arterial remodeling in other cardiovascular diseases. The objective of this work is to characterize how cysteine cathepsins and thrombospondin-1 contribute to SCD-mediated arterial remodeling and PAD. In Aim 1, a murine SCD transgenic mouse model will be used to mechanically characterize the lifelong arterial remodeling that occurs in SCD. In Aim 2, we will determine the markers that mediate SCD-remodeling by using chimeric SCD and cathepsin knockout mouse lines and mechanical tests. Histological methods will be used to further characterize the impacts of arterial remodeling by cathepsin expression or the TSP-1/CTGF pathway. In Aim 3, the utility of inhibiting the TSP-1/CTGF pathway in protecting vascular integrity will be explored in TSP-1 knockout animals. Ultimately the mechanisms explored in the proposed studies will advance current knowledge about the progression of SCD and PAD vascular remodeling, and the development of therapies that exploit these complex interactions to protect against or prevent destructive vascular remodeling.