University of Notre Dame
Browse
- No file added yet -

Exploring the Regulation and Role of the Signaling and Epigenetic Modulator S1P in Pulmonary Hypertension Lung Vasculature

Download (32.14 MB)
thesis
posted on 2022-04-07, 00:00 authored by Arambage Dushani Ranasinghe

Pulmonary arterial hypertension (PAH) is a progressive, incurable and devastating cardiopulmonary vascular disease with a 3-year survival rate <60%. Accumulation of risk factors to the pulmonary vasculature can lead to uncontrolled pulmonary arterial smooth muscle cell (PASMC) proliferation. Unfortunately, current PAH therapy offers only symptomatic relief. Thus, the underlying mechanism mediating the pathophysiological influences in PAH that modulate pulmonary vascular remodeling should be explored.

The bioactive sphingolipid, sphingosine-1-phosphate (S1P), a microvascular and immuno-modulator associated with vascular remodeling in PAH. Along with plasma S1P, both S1P generation catalyzing enzymes, SPHK expressions are reported to be elevated in remodeled pulmonary arteries of patients with IPAH. Here, we identified Endothelial Monocyte Activating Polypeptide II (EMAP II) as a strategic early regulator of SPHKs. This study establishes two coherent signaling pathways and subcellular activation for each isoenzyme. Unique identification of EMAP II mediated tissue injury response through triggering a bimodal phosphorylation of sphingosine generating S1P in a two-pronged manner by modulating both phosphorylation and transcriptional regulation of the S1P synthesis catalyzing kinase SPHK isoforms and downstream targets was demonstrated. Our findings are an important discovery for PAH, as novel and epigenetic roles for SPHK’s were identified and represents a new therapeutic target that could provide opportunities for the development of novel PAH therapies.

History

Date Modified

2022-05-03

Defense Date

2022-04-01

CIP Code

  • 26.0202

Research Director(s)

Margaret Schwarz

Committee Members

Paul Huber

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier

1313542059

Library Record

6208851

OCLC Number

1313542059

Program Name

  • Chemistry and Biochemistry

Usage metrics

    Dissertations

    Categories

    No categories selected

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC