NHLBI Comprehensive
Sickle Cell Centers

Other NHLBI Funded Research at CSCCs

Boston CSCC Research

• Effect of Pulse Butyrate on HbF and F-cells in Patients with Sickle Cell Anemia
• Investigator: Dr. Susan Perrine
• Aims:
  • Determine if addition of pulse butyrate increases percent HbF and percent F-cells in patients with sickle cell anemia, by absolute levels of 5% and 10% respectively, above these levels on standard therapy with hydroxyurea.
  • Determine whether several minor endpoints are different between the two treatment arms.
  • Determine whether clinical events are decreased with addition of the second therapeutic compared to standard treatment with hydroxyurea alone.
• Study Abstract

• The Role of NO in Vascular Responses in a Sickle Cell Transgenic Mouse
• Investigator: Dr. Harrison Farber
• Aims:
  • Define the role of NO in vascular responses and vaso-occlusive events in a sickle cell transgenic mouse by correlating functional assays, lung histology and animal mortality with changes in NO metabolism at baseline and during crisis induced by hypoxia.
  • Define the effect of pharmacological manipulation of ACS-like crisis in a sickle cell transgenic mouse using a) NOS substrate (arginine), NOS cofactors (BH4), NOS inhibitors and inhaled NO; or b) antioxidants (glutathione, OTC, EUK-8) and examining functional assays, lung histology and animal mortality at baseline and during crisis induced by hypoxia.
  • Define the importance of NO metabolism and oxidative stress in a sickle cell transgenic mouse by interbreeding it with: a) a NOS3 (or NOS2) deficient mouse; b) a glutathione peroxidase (GPx-1) deficient mouse; or c) a glucose-6-phosphate dehydrogenase (G6PD) mutant mouse and examining functional assays, lung histology and animal mortality at baseline and during induced crisis.
• Study Abstract

• The Adhesive Properties of Sickle Erythrocytes
• Investigators: Drs. David E. Golan and Gilda A. Barabino
• Aims:
  • Study membrane protein and lipid dynamics in sickle erythrocytes.
  • Study adhesive interactions between sickle erythrocytes and activated vascular endothelial cells.
  • Study adhesive interactions between sickle erythrocytes and activated T lymphocytes.
• Study Abstract

Bronx CSCC Research

• MRI and NIRS in SS Patients and Mice
• Investigator: Mary Fabry, MD
• Aims:
  • Test the limits of the hypothesis that the level of HbF, arginine in diet, and hydroxyurea all affect perfusion and blood oxygenation, albeit through different mechanisms.
• Study Abstract

• Sickle Cell Adhesion
• Investigator: D.K. Kaul, MD
• Aims:
  • Test the hypothesis that endothelial activation and damage is accompanied by expression of specific adhesion molecules that modulate SS cell adhesion to endothelium in vivo.
  • Test the hypothesis that sickle cell density classes are characterized by heterogenous distribution of adhesion receptors affecting their propensity to adhesion.
  • Test the hypothesis that NO will modulate red cell adhesion in vivo.
• Study Abstract

Cincinnati CSCC Research

• Dipyridamole/Magnesium to Improve Sickle Cell Hydration
• Principal Investigator: Karen Kalinyak, MD
  Co-Investigator: Clinton H. Joiner, MD, PhD
  Co-Investigator: Robert D. Franco, PhD
  
• Aims:
  • Test the therapeutic potential of dipyridamole, which inhibits sickling-induced cation leaks, and magnesium, which inhibits KCC, to improve SS RBC hydration in vivo.
• Study Abstract

• In Vivo Hydration Changes in Hb SS and SC Cells
• Principal Investigator: Robert D. Franco, PhD
  Co-Investigator: Clinton H. Joiner, MD, PhD
  
• Aims:
  • Examine the rate and mechanisms of hydration changes of SS RBC in vivo, using biotin label techniques.
• Study Abstract

• KCI Cotransport Regulation in Red Cells
• Principal Investigator: Clinton H. Joiner, MD, PhD
  Co-Investigator: Kathleen Anderson, PhD
  
• Aims:
  • Compare KCC in SS and AA retics, examining the relationship between VSP and physiological stimuli of KCC to test the hypotheses that the VSP in SS retics is abnormal relative to AA retics and that these abnormalities result from the oxidative damage known to occur in SS RBC.
  • Examine the functional properties of several splicing isoforms of KCC1 identified in erythroid cells, testing the hypothesis that these isotypes differ in their response to volume stimuli.
  • Determine the volume responsive elements in hKCC1.
• Study Abstract

• KC1 Cotransporter Gene Expression.
• Principal Investigator: Dao Pan, PhD
  Co-Investigator: Clinton H. Joiner, MD, PhD
  Co-Investigator: Patrick Gallagher, MD
  
• Aims:
  • Characterize the temporal sequence and level of expression of KCC1 and its isotypes during erythroid differentiation, comparing AA and SS cells.
  • Determine the critical cis elements regulating transcription of the human gene encoding KCC isoform 1.
  • Characterize the trans-acting factors that bind the genetic elements identified in aim 2.
• Study Abstract

Duke/UNC CSCC Research

• Allogeneic Stem Cell Transplantation for adult patients with Sickle Cell Disease
• Investigator: David Rizzieri, MD and Mitchell Horwitz, MD
• Aims:
  • Evaluate the safety, feasibility, and engraftment rate of transplantation using in vivo alemtuzumab followed by concomitantly administered fludarabine and cyclophosphamide as a conditioning regimen prior to HLA matched sibling peripheral blood progenitor cell infusion with alemtuzumab in the bag (in vivo and in vitro T cell depletion).
  • Perform a preliminary cost analysis of non-myeloablative transplantation in sickle cell disease. This determination will be conducted through a comparison of costs associated with treatment of sickle cell disease by non-myeloablative transplantation versus those associated with conventional care of patients with sickle cell disease considered eligible for this trial, but not enrolled.
  • Define the kinetics of immune reconstitution in sickle cell patients. Immune reconstitution will be measured by recovery of: a) Lymphocyte subsets (CD4 and CD8), b) Mitogen induced proliferation of T lymphocytes, c) Alloreactive T lymphocytes, d) Viral antigen specific T lymphocytes. We will further investigate whether recovery of T-cells occurs through a central (thymic) mechanism or peripheral expansion of donor T-cells using the T-cell receptor excision circle (TRECs) analysis.
• Study Abstract

• Priapism in Boys and Young Men: Incidence and Prevalence
• Investigator: Rupa Redding-Lallinger, MD
• Aims:
  • Define the incidence of priapism in relationship to the physical and hormonal developmental stages of puberty and early maturity.
  • Explore the relationship between priapism and psychological adjustment.
  • Rigorously compare the use of pseudoephedrine to placebo, and leuprolide to exchange transfusion for the prevention of priapism.
• Study Abstract

• Activation of cAMP-mediated Sickle Cell Adhesion
• Investigator: Leslie V. Parise, PhD
• Aims:
  • Establish the basis for epinephrine-responsive and non-responsive RBCs from different sickle cell patients.
  • Identify the epinephrine receptor subtype(s) that stimulate SS RBC adhesion and identify additional naturally occurring agonists and agonist receptors that induce this process.
  • Map the cAMP-dependent signaling pathway(s) mediating stimulated sickle cell adhesion to laminin.
  • Identify additional vascular proteins that support cAMP-stimulated SS RBC adhesion and the receptors/sites mediating these adhesive interactions.
  • Determine the role of cAMP-stimulated SS RBC adhesion in an in vivo system.
• Study Abstract

• Ribozyme-mediated Repair of Sickle ß–globin RNA and DNA
• Investigator: Bruce A. Sullenger, PhD
• Aims:
  • Evaluate the trans-splicing activity of group I intron variants and expression cassettes and identify those with enhanced ability to repair sickle ß–globin transcripts in cell culture.
  • Generate derivatives of the Lactococcus lactis group II intron RNP that can insert wild type ß–globin exons into mutant ß–globin genes in E. coli.
  • Evaluate the ability of group II intron RNPs to repair mutant ß–globin genes in mammalian cells by exon insertion following direct transfection of the reconstituted RNPs and following expression of the intron and the intron-encoded protein in human cells.
• Study Abstract

Marian Anderson CSCC Research

• Incidence of Vaso-Occlusive and Other Pain and its Characteristics in Infants and Young Children with SCD
• Investigator: Carlton Dampier, MD and Elizabeth Ely, PhD, RN
• Aims:
  • Expand our knowledge of the incidence of vaso-occlusive and other pain and its characteristics in infants and young children with SCD using parental daily reports.
  • Examine the relationship between the incidence and/or frequency of sickle pain in these infants and young children and various hematologic and biologic parameters.
  • Develop, implement, evaluate, and disseminate a parent-mediated home pain management protocol for the management of sickle pain in infants and young children.
• Study Abstract

• Correlation Between Biologic Markers and the Onset of Microvessel Occlusion Leading to Pain
• Investigator: Marie J. Stuart, MD and B.N.Y. Setty, PhD
• Aims:
  • Identify in a longitudinal prospective manner any correlation between certain biologic markers and the onset of microvessel occlusion leading to pain.
  • Provide a unique look at the temporal sequence of changes in adherence, endothelial, platelet, white cell, and hemostatic activation in infants as the protective effects of HbF decline, and the subject begins to “cope” with the unfolding systemic effects of HbS polymerization.
• Study Abstract

• Preliminary Relationship Between Erythrocyte Phosphatidylserine (PS) and Vaso-Occlusive Crisis (VOC)
• Investigator: B.N.Y. Setty, PhD, Saul Surrey, PhD, and Marie J. Stuart, MD
• Aims:
  • Evaluate endothelial PSR regulation and its interaction with PS-positive RBCs, initially using ionophore-scrambled HbAA controls red cells, such that red cell PS alone will presumably provide the adhesive interactions with the major EC counter-receptors.
  • Dissect the specific domain(s) on the TSP molecule with which PS-positive RBCs interact.
  • Assess for PSR (antigen, mRNA, and functional studies) on circulating endothelial cells (CECs) both in steady-state and VOC.
  • Examine a recently proposed hypothesis that the endothelium in SCD is in a state of anti-apoptotic tone by performing micro-capture quantitative assays for endothelial PS vesicles and an evaluation of CECs.
• Study Abstract

• Hydroxyurea and Periodic Phlebotomy for the Treatment of Pain Associated with HbSC
• Investigator: Marie J. Stuart, MD and Carlton Dampier, MD
• Aims:
  • Determine whether oral Hydroxyurea (HU) therapy and periodic phlebotomy, compared to HU alone over an 18 month period, will decrease self-reported pain rates in symptomatic patients with HbSC disease, as measured by an increase in the median duration between painful episodes.
  • Determine whether there will be signs of amelioration or organ damage as a result of these therapies; such as a potential partial return of splenic function, non-progression of proliferative retinopathy and/or avascular osteonecrosis.
• Study Abstract

Northern California CSCC Research

• Construction of Sickle Cell Anemia Mice Carrying Chromosomes from the Human Sickle Cell Anemia Haplotypes
• Investigator: Y.W. Kan MD, DSc
• Aims:
  • Construct mouse models of sickle cell anemia that carry the different human sickle cell haplotypes.
• Study Abstract

• Regulation of Sickle Cell Phospholipid Organization
• Investigator: Frans Kuypers, PhD
• Aims:
  • Assess the influence of the increased presence of inflammatory lipid mediators in SCD on the loss of phospholipid asymmetry in subpopulations of sickle cells. 
  • Investigate the role of intracellular signaling pathways in the erythrocyte in the regulation of the flipase and the scramblase.
  • Investigate the role of altered erythrocyte lipids on cell-cell interaction and physiological processes in the circulation.
• Study Abstract

• Safety Trial of a Secretory Phospoholipase A2 Inhibitor in Sickle Cell Disease
• Investigator: Lori Styles, MD
• Aims:
  • Assess the safety of a phospholipase (sPLA2) inhibitor in sickle cell patients at risk for acute chest syndrome.
• Study Abstract

• Genetic Predictors for Stroke in Adults with Sickle Cell
• Investigator: Carolyn Hoppe, MD
• Aims:
  • Identify genes influencing stroke risk in adults with SCA, using a candidate gene approach.
  • Determine risk haplotypes and gene-gene interactions that influence stroke risk in adult SCA.
  • Probe for associations between candidate genes and neurocognitive deficits in adults with SCA.
• Study Abstract

St Jude CSCC Research

• Combination Treatment with Hydroxyurea and Magnesium
• Investigator: Winfred Wang, MD and Jane Hankins, MD
• Aims:
  • Determine the maximal tolerated dose of magnesium pidolate in combination with hydroxyurea.
  • Determine the effect of the combination of hydroxyurea and magnesium on hematological parameters and red cell characteristics.
• Study Abstract

• Pathogenesis and Molecular Expression of Pneumococcal Infection in Sickle Cell Disease
• Investigator: Elaine Tuomanen, MD
• Aims:
  • Evaluate the pathophysiological and molecular events that underlie the increased susceptibility to pneumococcal infection. 
  • Determine the impact of penicillin prophylaxis, pneumococcal vaccination and specific antimicrobial therapy on the incidence of antibiotic tolerance and/or resistance of pneumococci presence in the pharynx of patients with sickle cell disease. 
• Study Abstract

• Molecular Mechanisms of Globin Gene Expression
• Investigator: John Cunningham, MD
• Aims:
  • Define the domains of EKLF involved in local and regional chromatin remodeling, transcription and globin gene switching in vivo.
  • Define the co-activators involved in the chromatin remodeling function of EKLF.
• Study Abstract

• Globin Gene Therapy
• Investigator: Derek Persons, MD, PhD
• Aims:
  • Develop and test lentiviral vectors containing different γ-globin cassettes with the goal of obtaining persistent, therapeutic γ-globin transgene expression in the maturing erythroid cells of sickle cell mice.
  • Establish the relative number of genetically corrected HSCs required for clinical improvement of murine sickle cell disease and then test an in vivo selection strategy utilizing the MGMT drug-resistance gene to achieve this goal in a non-myeloablative setting.
• Study Abstract

Southwestern CSCC Research

• Randomized Trial of Intravenous Ketorolac Versus Oral Ibuprofen for Painful Crisis
• Investigator: Charles T. Quinn, MD
• Aims:
  • Determine whether ketorolac decreases the time to a 50% reduction in reported pain intensity more quickly than oral ibuprofen.
  • Determine whether ketorolac is safe for children with SCD.
  • Determine whether secretory phospholipase A2 (sPLA2) predicts impending acute chest syndrome.
• Study Abstract

• Preclinical evaluation of gene therapy for Sickle Cell Disease
• Investigator: Victor Garcia, PhD
• Aims:
  • Develop lentivirus vectors for the efficient transduction of human γ-globin genes that express at high level when integrated as single copy genes.
  • Evaluate, in vitro, the human γ-globin vectors developed in specific aim 1 using hematopoietic progenitor cells from SC patients.
  • Perform the preclinical evaluation of SC gene therapy using a human/mouse xenograft model of bone marrow transplantation.
• Study Abstract

• Disregulation of the Sickle Cell Membrane Skeleton
• Investigator: Steven R. Goodman, PhD
• Aims:
  • Identify the cysteines and lysines involved in E2 and E3 activity and target sites in alpha spectrin 20/21 utlilizing proteomics technologies.
  • Determine the role of spectrin ubiquitination in regulating heterodimer formation and spectrin-4.1 or adducin-actin ternary complex formation and disassembly, respectively.
• Study Abstract