Author ORCID Identifier

orcid.org/0000-0001-9976-2985

Date of Graduation

5-2017

Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Yang Xia, M.D., Ph.D.

Committee Member

Rodney Kellems, Ph.D.

Committee Member

Chengchi Lee, Ph.D.

Committee Member

Dorothy Lewis, Ph.D.

Committee Member

Zheng Chen, Ph.D.

Abstract

Adenosine is a ubiquitous nucleoside in almost all the cells throughout our bodies. It is highly induced particularly under hypoxia or energy depletion conditions. Adenosine functions as a critical ligand, after binding to membrane-associated adenosine receptors, adenosine initiates a downstream signaling cascade and subsequently contributes to functions of nervous system, immune response, vascular function and even metabolism.

Hypoxia is a condition with limited O2 availability in the whole body or a region of the body. It is a major consequence of many respiratory and cardiovascular diseases, as well as for people living and working at high altitudes or other low O2 conditions. Without intervention, it can progress to pulmonary and cerebral edema, stroke, cardiovascular dysfunction and death. Although hypoxia-induced tissue damage is a serious condition with high morbidity and mortality, safe and effective mechanism-based therapies are limited.

The erythrocyte is the most abundant circulating cell type and functions as the only cell-type responsible for O2 availability in peripheral tissues. Its fundamental function, O2 release capacity and O2 delivery capacity, is determined by hemoglobin-O2 binding affinity and cell number, respectively.

Although adenosine signaling is beneficial under stress conditions in various organs and tissues via activation of different adenosine receptors, its significance and functional role in the erythroid lineage, particularly under stress conditions, are still unclear.

My dissertation employing multi-disciplinary approaches including human studies, novel genetic tools, and sophisticated pharmacological studies coupled with metabolomic profiling shows for the first time that 1) CD73-dependent elevation of plasma adenosine signaling via erythrocyte specific ADORA2B coupled with AMP-activated protein kinase is a key mechanism for hypoxia adaptation via induction of 2,3-BPG production with O2 release to counteract severe hypoxia. 2) Adenosine signaling via erythroid ADORA2B is a previously unrecognized purinergic signaling responsible for stress erythropoiesis by regulation of erythroid commitment in a hypoxia-inducible factor 1-alpha dependent manner.

Thus, my research has identified that adenosine signaling functions as a novel molecular mechanism involved in the regulation of erythrocyte O2 release capacity and O2 delivery capacity, providing therapeutic possibilities to enhance O2 availability and prevent stress-induced tissue damage and inflammation, a strong foundation for future clinical trials to treat diseases associated with hypoxia or hematology disorders provided by my doctoral work.

Keywords

Hypoxia, adenosine signaling, metabolomics, erythroid progenitors, stress erythropiesis, high altitude, erythrocyte

Available for download on Friday, May 25, 2018

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