The goal of the proposed research is the development of novel approaches to ameliorate erythrocyte sickling in individuals with sickle cell disease (SCD). Although this disease was discovered more than a century ago, we still lack effective mechanism-based therapies. This disease is the most prevalent inherited genetic disorder and affects millions worldwide. As an important mission of NIH is to develop highly innovative treatments for this disease, the goal of the proposed work should be of high priority. Research proposed here is based on unexpected discoveries resulting from an unbiased, high-throughput metabolomic screen that identified several metabolites including adenosine (Ado), sphingosine-1-phosphate (S1P) and 2,3- diphosphoglycerate (2,3-DPG) that are highly elevated in the blood of mice and humans with SCD. Follow-up studies showed that these three elevated metabolites collaboratively work together to promote sickling, the central pathogenic process of the disease. The project has interrelated goals to translate our findings into innovative therapeutics for SCD by providing new insight into disease pathogenesis.
In AIM I, we propose to use both pharmacological and genetic approaches to determine whether excess Ado signaling via A2BR induces 2,3-DPG production by protein kinase A (PKA)-dependent phosphorylation of key enzymes involved in 2,3-DPG generation. These studies will provide novel mechanism underlying Ado signaling-mediated 2,3-DPG induction and add a new chapter to erythrocyte physiology and pathology.
In AIM II, we will explore different approaches including genetic, pharmacological, cellular, biochemical, and high throughput robotic co- crystallography coupled with spectral functional analysis to determine how S1P: 1) functions as an intracellular allosteric modulator to regulate Hb-O2 affinity and 2) functions via extracellular S1P receptors to induce inflammation. Additional experiments encompass a set of preclinical studies to test the efficacy and safety of lowering S1P by specific antagonists in SCD mice. These studies are expected to provide the foundation for appropriate clinical trials in humans with SCD. Third, the molecular basis underlying elevated S1P inside RBCs and in plasma will be investigated. Briefly, we propose to test a novel hypothesis that A2BR functions upstream to induce S1P production within RBCs and that activated platelets and complement activation-induced intravascular hemolysis underlie the further elevation of S1P in plasma.
In AIM I V, we propose translational studies to conduct an analysis of approximately 235 adult blood samples obtained from a large cohort of SCD patients by collaborating with the NHLBI to determine whether these newly identified elevated metabolites are pathogenic biomarkers correlating to disease severity and phenotypic variation. Overall, the proposed preclinical animal studies and translational human studies are expected to reveal important therapeutic targets in the medical management of SCD patients.
Sickle cell disease is an inherited blood disorder that results from a mutation in hemoglobin, the protein that carries oxygen in red blood cells throughout our bodies. The mutant hemoglobin causes the red blood cells to acquire an unusual sickle shape that hinders movement through blood vessels. The clumps of sickled cells block blood flow resulting in pain, serious infections, and organ damage. Research in the laboratory of the principal investigator has discovered a process that contributes to enhanced red blood cell sickling, inflammation and progression of the disease and has identified a mechanism-based therapeutic approach to inhibit this process.
|Zhao, Shushan; Adebiyi, Morayo G; Zhang, Yujin et al. (2018) Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease. FASEB J 32:2855-2865|
|Liu, Hong; Adebiyi, Morayo; Liu, Rong Rong et al. (2018) Elevated ecto-5'-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease. Blood Adv 2:1957-1968|
|Liu, Chen; Alessandro, Angelo D'; Xia, Yang (2017) Metabolomic Approach in Probing Drug Candidates. Curr Top Med Chem 17:1741-1749|
|Sun, Kaiqi; Liu, Hong; Song, Anren et al. (2017) Erythrocyte purinergic signaling components underlie hypoxia adaptation. J Appl Physiol (1985) 123:951-956|
|Sun, Kaiqi; D'Alessandro, Angelo; Ahmed, Mostafa H et al. (2017) Structural and Functional Insight of Sphingosine 1-Phosphate-Mediated Pathogenic Metabolic Reprogramming in Sickle Cell Disease. Sci Rep 7:15281|
|Wang, Wenjuan; Yuan, Yuan; Zheng, Haiqing et al. (2017) A Pilot Study of Noninvasive Prenatal Diagnosis of Alpha- and Beta-Thalassemia with Target Capture Sequencing of Cell-Free Fetal DNA in Maternal Blood. Genet Test Mol Biomarkers 21:433-439|
|Liu, Chen; Kellems, Rodney E; Xia, Yang (2017) Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase. Am J Hypertens 30:756-764|
|Sun, Kaiqi; D'alessandro, Angelo; Xia, Yang (2017) Purinergic control of red blood cell metabolism: novel strategies to improve red cell storage quality. Blood Transfus 15:535-542|
|Huang, Aji; Wu, Hongyu; Iriyama, Takayuki et al. (2017) Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia. Hypertension 70:209-218|
|Song, Anren; Zhang, Yujin; Han, Leng et al. (2017) Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun 8:14108|
Showing the most recent 10 out of 34 publications