1. Analysis of NIH-supported Sickle Cell Disease Portfolio Manjit Hanspal, Ph.D. Division of Blood Diseases & Resources Nara Gavini, Ph.D. Center for Translation Research and Implementation Science SCD Advisory Committee Meeting October 17, 2014

2. Data generated from QVR (Query View Report): QVR is a web-based system that is available to the NIH extramural staff to query the NIH database, view data and produce reports 295 Records were obtained (we identified 48 grants as not directly addressing SCD research and hence were deleted) 247 grants were subjected to further analysis SCD grants awarded by NIH in FY 2007-2013

3. Funding, $: 225,092,358 19,298,434 21,437,026 6,247,049 135,500 % of Total Funding: 83 7 8 2 <1 Number of Grants RPGs Career Small Bus. Center Conference

4. 2007 2008 2009 2010 2011 2012 2013 Number of Grants ARRA grants Time line of SCD grants funded (2007-2013)

5. QVR-generated data for the 170 RPGs was analyzed using IN-SPIRE IN-SPIRE: software for text analysis and visualization; identifies key thematic terms in the document, and then visually organizes the documents based upon term usage.

6. Pain management /intervention Neurological/organ dysfunction Adhesion/vascular SS-RBC Pathology Globin gene expression Galaxy View

7. Pain management/ intervention Neurological/organ dysfunction Adhesion/vascular SS-RBC Pathology Globin gene expression ThemeView Classic

8. RPGs 83% Career Dev & Training 7% Center 2% Small Business 8% Conference <1% Adhesion/Vascular 35% Globin Gene 20% Neurological/Organ 27% SS-RBC Pathology 9% Pain 9% Funding distribution among the various grant mechanisms Distribution of RPG funds among the 5 sub-clusters

9. Sickle Red Blood Cell Pathology Cluster 22 grants, totaling $19,955,098 Pathology of abnormal RBCs (SS-RBCs): abnormal Hb polymerization inside the RBC results in irregular cell shape, stiffening of the RBC membrane, altered adhesion properties and abnormal blood flow Mechanisms that contribute to the abnormal rheology of blood Using microfluidic devices and sophisticated mathematical simulations, investigators are studying the effects of modulating RBC aggregation; RBC-endothelium adhesion; sickling kinetics, and oxygen delivery on occlusion formation and reversal Developing multiscale modeling methodology for quantifying the biophysical characteristics of SS-RBCs.

10. Using computer modeling together with structural biology, biochemistry, biophysics, and molecular biology techniques -to obtain a detailed structural description of oxygen binding to Hb subunits, and -determine how binding to one subunit can alter the accessibility and reactivity of heme-iron atoms in adjacent subunits Sickle Red Blood Cell Pathology Cluster (contd.) To improve vascular tone, cell adhesion, and cell activation in SCD by identifying remediable SS-RBC abnormalities Develop a new generation of Hb-based oxygen carriers and a new approach for SCD treatment

11. Globin Gene Expression Cluster Understanding regulatory mechanisms of globin gene expression: Mutations in the beta-globin gene LCR Transcription factors involved in globin gene regulation Epigenetic factors such as DNA methylation & histone deacetylation Effect of higher order chromatin structure on gene expression Therapeutic potential of chromatin looping Role of microRNAs in globin gene regulation Reversal of fetal globin gene silencing BCL11A has been identified as a direct regulator of HbF level Studies are being pursued to exploit BCL11A and its binding partners as targets for therapeutics 43 grants, totaling $48,031,881

12. Adhesion and Vascular Dysfunction cluster 61 Grants, totaling $85,438,430 SCD is a hemoglobin disorder that is associated with a complex vascular pathophysiology that results in multifocal vascular occlusion and end organ dysfunction Investigating the role of leukocytes in vascular occlusion Cellular and molecular events that trigger vaso-occlusion Tissue ischemia Identification of biomarkers as well as prevention and treatment of endothelial barrier dysfunction Development of interventions for the management of vascular complications in SCD

13. Pain Management and Intervention Cluster Investigating hematological factors as well as the underlying genetic variability in patients that may contribute to the manifestation of severe VOEs. Some of the intervention strategies for acute sickle cell pain episodes that are being studied include analgesics, intravenous immune globulin, Eptifibatide (a platelet aggregation inhibitor), and intravenous magnesium for vaso-occlusive crisis. Basic research on pain involves development of preclinical models of pain; and studies of pain regulation and dysregulation 18 grants, totaling $21,686,194 Recurrent vaso-occlusive pain episodes (VOEs) are the hallmark feature of SCD and the leading source of morbidity in individuals with SCD Heterogeneity of VOEs includes frequency, duration, intensity, and extent of disability from VOEs

14. A subset of projects in this cluster is investigating racial disparities in the quality of health care for treatment of pain. Some projects are developing web tools and wireless technology to empower SCD patients to improve care communications, especially for at risk youths with SCD Pain Management and Intervention Cluster (contd.)

15. Neurological complications and organ-specific dysfunction Cluster: 27 grants, totaling $57,138,756 Neurocognitive complications of SCD in children -Stroke -silent cerebral infarct (SCI) -cognitive impairment Studies designed to examine hydroxyurea use in children include the effect of HU therapy when initiated in infancy: -on growth, development, and morbidity in children with SCD, -stroke prevention in children with abnormally high transcranial Doppler (TCD) measurement, or -to prevent future vascular flow abnormalities in children with normal TCD velocities.

16. Neurological complications and organ-specific dysfunction Cluster (contd): Investigating various complications of sickle nephropathy, pulmonary hypertension, and acute chest syndrome (ACS) -Feasibility study of Regadenoson for treatment of ACS -Elucidating the role of Endothelin-1 with regards to inflammation, vasculopathy, lung and kidney injury and pain. To elucidate the effects that asthma and sleep disordered breathing have on SCD morbidity: -Studies designed to determine if asthma risk factors are associated with an increased incidence of pain and ACS episodes.

17. SUMMARY For SCD research, the NIH supported 247 de novo grants totaling $279,368,368 for Fiscal Years 2007 through 2013 NIH-supported SCD portfolio consists of RPGs; Career development & Training grants; Small business/Technology development grants; Large Center grants; and Conference grants A large portion of the portfolio is dedicated to RPGs focusing on basic, translational and clinical studies of SCD NHLBI is the largest funder of SCD research at NIH contributing 77% of total funds; followed by NIDDK that is contributing 13% of total funds. The remaining 10% of the funds are contributed by all other NIH ICs combined NHLBI funds all aspects of SCD research

18. NHLBI NIDDK Pain management /intervention Neurological/organ dysfunction Adhesion/vascular SS-RBC Pathology Globin gene expression Pain management /intervention Neurological/organ dysfunction Adhesion/vascular SS-RBC Pathology Globin gene expression Comparison of NHLBI and NIDDK SCD portfolio