Patrick Belvitch, MD
Current Support: K08 HL135318-01 Belvitch (PI)
01/01/2017 – 12/31/2021
NIH/NHLBI Protein Regulation and Cytoskeletal Dynamics of Pulmonary Endothelial Barrier Function
This project focuses on the characterization of a three cytoskeletal regulatory proteins, myosin light chain kinase, cortactin and the Arp 2/3 complex and their integrated role in generating endothelial cell membrane structures to ultimately determine barrier function. The goal of this research is to better understand the pathophysiologic mechanisms responsible for pulmonary vascular leak and recovery of barrier function in ARDS.
1. Belvitch P, Brown, ME, Brinley B Letsiou E, Rizzo AN, Garcia, JGN and Dudek S.M. The ARP 2/3 complex mediates endothelial barrier function and recovery. Pulmonary Circulation. 2016 Feb 1; vol. 7, 1: pp. 200-210.
2. Belvitch P,Adyshev D, Elangovan VR, Brown ME, Naureckas C, Rizzo AN, Siegler JH, Garcia JG, Dudek SM. Proline-rich region of non-muscle myosin light chain kinase modulates kinase activity and endothelial cytoskeletal dynamics. Microvascular Research. 2014 Jul 27;95C:94-102. PMID: 25072537
3. Belvitch P and Dudek, S.M. Role of FAK in S1P-Regulated Endothelial Permeability. Microvascular Research. 2012 Jan;83(1):22-30. PMID: 21925517
4. Letsiou E, Sammani S, Wang H, Belvitch P, Dudek SM. Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury. Translational Research. 2016 Sep 13. pii: S1931-5244(16)30199-2. PMID: 27693468.
5. Sun X, Singleton PA, Letsiou E, Zhao J, Belvitch P, Sammani S, Chiang ET, Moreno-Vinasco L, Wade MS, Zhou T, Liu B, Parastatidis I, Thomson L, Ischiropoulos H, Natarajan V, Jacobson JR, Machado RF, Dudek SM, Garcia JG. Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury.
Am J Respir Cell Mol Biol. 2012 Nov;47(5):628-36. PMID: 22771388
Steven Dudek, MD
Current Support: P01 HL126609 Joe G.N. Garcia (PI) Dudek (Project 2 PI)
NIH/NHLBI Cytoskeletal Regulation of Lung Endothelial Pathobiology
Project 2: Mechanisms of Peripheral Remodeling of the EC Cytoskeleton
The project will study the critical roles of actin-regulatory proteins (cortactin, EVL, c-Abl) in the cytoskeleton remodeling and lamellipodia formation that restores pulmonary endothelial barrier integrity.
Role: Project Leader PI (20%)
R01 HL111656-01 Roberto Machado (PI) 02/05/13- 04/30/21
NIH/NHLBI Vascular Targeted Genomic and Genetic Strategies for Acute Chest Syndrome
The major goal of this project is to investigate the role of new genetic markers as risk factors for the development of acute chest syndrome, a major cause of death in patients with sickle cell disease. It will also investigate the role of genetic markers as a tool to identify patients with acute chest syndrome.
Role: Co-I (5%)
R01 HL133413 Mahendra Damarla (PI) 07/01/2016- 06/30/2021
NIH/NHLBI Targeting Divergent Roles of Caspase 3 to Promote Endothelial Barrier Integrity
This project hypothesizes that MK2 dependent phosphorylation of active caspase 3, and subsequent nuclear translocation, converts its barrier protective cytoskeletal reorganization function to promoting apoptosis thereby stimulating pulmonary vascular permeability.Multiple in vitro (thrombin and lipopolysaccharide) and in vivo (endotoxemia and cecal-ligation and puncture) models of endothelial barrier dysfunction to mimic sepsis-induced ARDS will be utilized.
Role: Co-investigator (2%)
Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, Garcia JGN. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: Roles for cortactin and myosin light chain kinase. J Biol Chem, 279:24692-700, 2004. PMCID: PMC2682440
Dudek SM, Chiang ET, Camp SM, Guo Y, Zhao J, Brown ME, Singleton PA, Wang L, Desai A, Arce FT, Lal R, Van Eyk JE, Imam SZ, Garcia JGN. Abl tyrosine kinase phosphorylates non-muscle myosin light chain kinase to regulate endothelial barrier function. Mol Biol Cell, 21:4042-56, 2010. PMCID: PMC2982111
Dudek SM, Muñoz NM, Desai A, Osan CM, Meliton AY, Leff AR. Group V phospholipase A2 mediates barrier disruption of human pulmonary endothelial cells caused by LPS in vitro. Am J Respir Cell Mol Biol, 44(3):361-8, 2011. PMCID: PMC3095937
Wang L, Sammani S, Moreno-Vinasco L, Letsiou E, Wang T, Camp SM, Bittman R, Garcia JGN, Dudek SM. FTY720 (S)-phosphonate preserves S1PR1 expression and exhibits superior barrier protection to FTY720 in acute lung injury. Crit Care Medicine, 42(3):e189-99, 2014. PMCID: PMC4144721
Letsiou E, Rizzo AN, Sammani S, Naureckas P, Jacobson JR, Garcia JG, Dudek SM. Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol, 308(3):L259-69, 2015. PMCID: PMC4338930
Dustin Fraidenburg, MD
Current Support: K08 HL133474 NIH/NHLBIFraidenburg (PI)
09/01/2016 – 07/31/2021
Role of NFATc3 in Altered Hypoxic Pulmonary Vasoconstriction during Acute Lung Injury
Lung inflammation and hypoxemia are major risk factors for mortality in acute respiratory distress syndrome (ARDS). Adequate blood oxygenation is dependent on effective matching of ventilation and perfusion in the lung microenvironment and, as an evolutionary mechanism, hypoxic pulmonary vasoconstriction is aimed at maintaining sufficient blood supply to the most effectively ventilated areas of the lung. The purpose of this proposal is to determine the mechanisms by which NFATc3 leads to impaired HPV during acute lung inflammation and injury.
Fraidenburg, D.R. and J.X.-J. Yuan. Hungry for more – Autophagy in the pathogenesis of PAH. Circ Res. Apr 12; 112(8): 1091-1093, 2013.
Smith, K.A., G. Voiriot, H. Tang, D.R. Fraidenburg, S. Song, H. Yamamura, Q. Guo, J. Wan, N.M. Pohl, M. Tauseef, R. Bodmer, K. Ocorr, P.A. Thistlethwaite, G.G. Haddad, F.L. Powell, A. Makino, D. Mehta, and J.X.-J. Yuan. Notch activation of Ca2+ signaling mediates hypoxic pulmonary vasoconstriction and pulmonary hypertension. Am J. Respir Cell Mol Biol. Sep; 53(3):355-67, 2015.
Fraidenburg, D.R. and R.F. Machado. Pulmonary hypertension in thalassemia syndromes. Ann NY Acad Sci. 2016 Mar;1368(1):127-39.
Tang, H., A. Yamamura, H. Yamamura, S. Song, D.R. Fraidenburg, J. Chen, Y. Gu, N. Pohl, T. Zhou, L. Perez, R. Ayon, A. Desai, D. Goltzman, F. Rischard, Z. Khalpey, S. Black, J.G.N. Garcia, A. Makino, and J.X.-J. Yuan. Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016 May 1; 310 (9): 846-59.
Fraidenburg, D.R., A.A. Desai, and J.X.-J. Yuan. Treatment of pulmonary arterial hypertension. In: “Goodman and Gilman’s The Pharmacological Basis of Therapeutics,” edited by L. Brunton, McGraw-Hill; New York, NY; 2017. (Book Chapter)
Jeffrey Jacobson, MD
Ongoing Research Support:
R01 HL147942-01A1 Jeffrey Jacobson Sphingolipids as Novel Therapeutic Targets in Radiation Lung Injury 04/05/2020 – 03/31/2024
Radiation-induced lung injury (RILI) is a common complication in patients administered thoracic radiotherapy that is associated with significant morbidity and mortality and for which effective therapies currently do not exist. We have developed a mouse model of RILI and identified signaling by sphingolipids as an important mediator of injury. In this proposal, studies will investigate mechanisms of sphingolipid-mediated lung injury in response to radiation which may ultimately yield more precise and effective RILI therapeutic strategies.
P01 HL126609 Garcia (Overall Program Director) 04/01/16 – 03/31/21 Cytoskeletal Regulation of Lung Endothelial Pathobiology
Project 3: Integrin Beta4 and Paxillin in EC Focal Adhesion Dynamics and Barrier Responses
This projected will investigate the role of integrin beta4 and paxillin as mediators of lung vascular permeability via modulation of focal adhesion dynamics. Cell and animal models will be employed and studies will include focus on single nucleotide polymorphisms and post-translational modifications that effect variable phenotypic responses of the lung endothelium to barrier-disruptive stimuli and may ultimately facilitate the development of new strategies and targets to limit the adverse effect of injured pulmonary circulation.
Role: Project co-I (Project PI: Cress)
Key Publications (5 selected):
1. Mitra S, Sammani S, Wang T, Boone DL, Meyer NJ, Dudek SM, Moreno-Vinasco L, Garcia JG, Jacobson JR. Role of GADD45a in Akt phosphorylation and ubiquitination following mechanical stress-induced vascular injury. Am J Resp Crit Care Med 2011, 184(9):1030-1040. PMCID: PMC3763933
2. Ephstein Y, Singleton P, Chen W, Wang L, Slagia R, Kanteti P, Dudek SM, Garcia JGN, Jacobson JR. Critical role for S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity. J Biol Chem 2013, 288(4): 2191-200. PMCID: PMC3554892
3. Chen W, Sharma R, Rizzo AN, Siegler JH, Garcia JGN, Jacobson JR. Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin. Am J Resp Cell Mol Biol 2014, 50(2): 328-36. PMCID: PMC3930946
4. Mathew B, Takekoshi D, Sammani S, Epshtein Y, Sharma R, Smith BD, Weichselbaum RR, Garcia JGN, Jacobson JR. Role of GADD45a in murine models of radiation and bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2015, 309(12):L1420-9. PMCID: PMC46833
5. Chen W, Epshtein Y, Ni X, Dull RO, Cress AE, Garcia JGN, Jacobson JR. Role of Integrin β4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress. Sci Rep 2015, 5:16529. PMCID: PMC4647208
Min Joo, MD, MPH
Current Support: 1R01HS024964-01 Joo (PI) 9/2016-7/2021
Total cost: $1,481,271
Reducing Diagnostic Error to Improve Patient Safety in COPD and Asthma (REDEFINE Study)
THE REDEFINE study is an innovative approach that aims to reduce DE and improve patient safety for patients with a diagnosis of COPD and asthma in an underserved primary care ambulatory setting. The approach includes guideline based recommendations including spirometry within the pragmatic framework of a busy primary care practice, addresses limitations in past efforts and newly identified barriers to reduce DE in asthma and COPD in an underserved population with multiple chronic medical conditions.
R01 HL136682-04 Fernando J. Martinez Cornell University and also COPD Foundation for this same study “The CAPTURE Study: Validating a unique COPD screening tool in primary care” 07/01/19 – 06/30/21
PCORI Krishnan(Lead PI) 2016-2020 (contract pending) budget: $13,768,625
Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
1. compare effectiveness of roflumilast versus azithromycin on all-cause hospitalizations or death
2. to determine secondary outcomes which include patient-reported measures of physical function, problems with sleep, fatigue, anxiety, and ability to perform usual activities, measured using the NIH-PROMIS instruments.
Role: Site-PI for UI Health
PCORI Krishnan(Lead PI) 7/2013-6/2016 (no cost extension)
PATient Navigator to rEduce Readmissions (PArTNER)
1. Develop, implement, and refine a multi-faceted stakeholder-supported PArTNER intervention to improve the patient experience during transitions out of the hospital at a MSI.
2. Compare the effectiveness of PArTNER vs. usual care on patient experience (co-primary outcomes: social support and anxiety) and secondary outcomes (e.g., hospital readmissions) in a clinical trial.
Role: Co-investigator (effort Year 1: 7.5%, Year 2: 5%, Year 3: 8%) direct costs: $1,472,020
- Min J Joo, Lisa K Sharp, David H Au, Todd A Lee, Marian L Fitzgibbon. Use of spirometry in the diagnosis of COPD: A qualitative study in primary care. J COPD 2013 [PMID: 23537230]
- Sruthi Adimadhyam, Glen T. Schumock, Surrey Walton, Min Joo, Joanne McKell, Todd A. Lee. Risk of arrhythmias associated with ipratropium bromide in children, adolescents, and young adults with asthma. Pharmacotherapy 2013 [PMID 23918239]
- Iulia D. Ursan, Jerry A. Krishnan, A. Simon Pickard, Elizabeth Calhoun, Robert DiDomenico, Valentin Prieto-Centurion, Jamie B. Sullivan, Lauren Valentino, Mark V. Williams, Min J Joo, on behalf of the PArTNER investigators. Engaging Patients and Caregivers to Design Transitional Care Management Services at a Minority Serving Institution, J. Health Care Poor Underserved, Feb 2016
- Kevin C. Wilson, Michael K. Gould, Jerry A. Krishnan, Cynthia M. Boyd, Jan L. Brozek, Colin R. Cooke, Ivor S. Douglas, Richard A. Goodman, Min J. Joo, Suzanne Lareau, Richard A. Mularski, Minal R. Patel, Richard M. Rosenfeld, Hasan Shanawani*, Christopher Slatore, Marianna Sockrider, Beth Sufian, Carey C. Thomson, and Renda Soylemez Wiener “An Official American Thoracic Society Workshop Report. A Framework for Addressing Multimorbidity in Clinical Practice Guidelines for Pulmonary Disease, Critical Illness, and Sleep Disorders”, Annals of the American Thoracic Society, Vol. 13, No. 3 (2016), pp. S12-S21. Mar 2016 [PMID 26963362]
- Samp JC, Joo MJ, Schumock GT, Calip GS, Pickard AS, Lee TA. Comparative effectiveness of long-acting beta2 -agonist combined with a long-acting muscarinic antagonist or inhaled corticosteroid in chronic obstructive pulmonary disease. Pharmacotherapy 2017 [PMID 28226405]
Jerry Krishnan, MD, PhD
- U01HL134042 (MPI, Gordeuk, Hsu, Hirschtick, Krishnan,Wandersman) NIH/NHLBI
Improving Sickle cell care in Adolescents & Adults in Chicago (ISAAC)
To conduct an implementation trial evaluating interventions using community health workers and technology to promote longitudinal care, increase use of hydroxyurea, and better treatment for sickle-cell related pain.
- (awarded; contract pending) (PI, Krishnan) Patient Centered Outcomes Research Institute
Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
To conduct a pragmatic trial to evaluate chronic roflumilast versus azithromycin therapy in high-risk patients with COPD, with a primary outcome of hospitalization or death. Secondary outcomes are patient-reported measures of physical function, problems with sleep, fatigue, anxiety, and ability to perform usual activities, measured using the NIH-PROMIS instruments. Participants will be followed up for a period of 6 months (minimum) to 36 months (maximum).
- AS-1307-05420 (PI, Krishnan), Patient Centered Outcomes Research Institute
Coordinated Healthcare Interventions for Childhood Asthma Gaps in Outcomes (CHICAGO) Trial
To test both provider- and patient-level interventions to improve clinically meaningful outcomes in a minority pediatric ED population with uncontrolled asthma.
- CE-1304-6490 (PI, Krishnan) Patient Centered Outcomes Research Institute
Comparative effectiveness of a PEer-Led O2 Infoline for patients and CAregivers (PELICAN)
To develop and test a peer-led telephone line intervention to improve adherence to oxygen therapy in patients with COPD recently discharged from the hospital. We will evaluate the comparative effectiveness of proactive vs. reactive PELICAN interventions vs. usual care on adherence to O2, assessed utilizing novel methodology, in a pragmatic clinical trial in collaboration with patients/caregivers, advocacy groups, a national O2 supplier, and other stakeholders.
- IH-12-11-4365 (PI, Krishnan) Patient Centered Outcomes Research Institute
PATient Navigator to rEduce Readmissions (PArTNER)
To develop and test a community health worker and peer-led telephone line intervention to improve patients experience and outcomes after hospital discharge at a minority serving institution. We will conduct a pragmatic clinical trial in collaboration with patients, patient advocacy groups, and other stakeholders.
- U10HL098096 (MPIs, Smith/Solway/ Krishnan/Pongracic)
Chicago Metropolitan AsthmaNet Consortium (CMAC)
The CMAC aims to 1) address important clinical management questions in asthma through trials that will help identify optimal therapies for a variety of asthma phenotypes, genotypes, and racial an ethnic backgrounds; 2) conduct small studies designed to advance novel asthma therapies and to investigate the mechanistic basis for interventions in asthma clinical trials; and 3) inform future clinical practice and updates to federal guidelines.
Roles: Multiple Principal Investigator and Core leader (Clinical Research Skills Development Core)
- ILCHI 60043659 (PI, Smith; UIC site PI, Krishnan)
American Lung Association
Illinois Consortium for the ALA-Airways Clinical Research Centers
To conduct clinical trials in asthma and COPD as part of the Airway Clinical Research Centers network.
- UG3 OD023189 (PI, Greenland, Winn, Daviglus, Ahsan)
Office of the Director, NIH
Illinois Precision Medicine Consortium
The objective is to serve as a Precision Medicine Initiative (PMI) Cohort Program HPO Enrollment Center. IPMC comprises 3 major Chicago-area academic institutions (Northwestern University, University of Chicago, and the University of Illinois at Chicago) and their healthcare provider organization (HPO) partners across Illinois.
Design of a pragmatic trial in minority children presenting to the emergency department with uncontrolled asthma: The CHICAGO Plan.
Krishnan JA, Martin MA, Lohff C, Mosnaim GS, Margellos-Anast H, DeLisa JA, McMahon K, Erwin K, Zun LS, Berbaum ML, McDermott M, Bracken NE, Kumar R, Margaret Paik S, Nyenhuis SM, Ignoffo S, Press VG, Pittsenbarger ZE, Thompson TM; CHICAGO Plan consortium..
Contemp Clin Trials. 2017 Mar 31;57:10-22.
Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline.
Wedzicha JA ERS Co-Chair, Miravitlles M, Hurst JR, Calverley PM, Albert RK, Anzueto A, Criner GJ, Papi A, Rabe KF, Rigau D, Sliwinski P, Tonia T, Vestbo J, Wilson KC, Krishnan JA ATS Co-Chair.
Eur Respir J. 2017 Mar 15;49(3).
Reducing Health Inequities in the U.S.: Recommendations From the NHLBI’s Health Inequities Think Tank Meeting.
Sampson UK, Kaplan RM, Cooper RS, Diez Roux AV, Marks JS, Engelgau MM, Peprah E, Mishoe H, Boulware LE, Felix KL, Califf RM, Flack JM, Cooper LA, Gracia JN, Henderson JA, Davidson KW, Krishnan JA, Lewis TT, Sanchez E, Luban NL, Vaccarino V, Wong WF, Wright JT Jr, Meyers D, Ogedegbe OG, Presley-Cantrell L, Chambers DA, Belis D, Bennett GC, Boyington JE, Creazzo TL, de Jesus JM, Krishnamurti C, Lowden MR, Punturieri A, Shero ST, Young NS, Zou S, Mensah GA.
J Am Coll Cardiol. 2016 Aug 2;68(5):517-24.
Using design methods to provide the care that people want and need.
Erwin K, Krishnan JA.
J Comp Eff Res. 2016 Jan;5(1):13-5.
American Thoracic Society and National Heart, Lung, and Blood Institute Implementation Research Workshop Report.
Bender BG, Krishnan JA, Chambers DA, Cloutier MM, Riekert KA, Rand CS, Schatz M, Thomson CC, Wilson SR, Apter A, Carson SS, George M, Gerald JK, Gerald L, Goss CH, Okelo SO, Mularski RA, Nguyen HQ, Patel MR, Szefler SJ, Weiss CH, Wilson KC, Freemer M.
Ann Am Thorac Soc. 2015 Dec;12(12):S213-21.
Irena Levitan, PhD
2004-2018 R01, NIH HLBI 073965 PI: I. Levitan
“Cholesterol regulation of endothelial K+ channels”,
The goals of this project are to elucidate the mechanisms of cholesterol-induced suppression of K+ channels.
- R01, NIH HLBI 083298 PI: I. Levitan , no cost extension
“Impact of dyslipidemia on endothelial biomechanics”
The goals of this project are to determine the mechanisms by which oxidized lipoproteins, particularly oxLDL, cause endothelial stiffening and affect endothelial force generation.
2014-2018 R01 GM110118-1(PI: Cho), NIH/NIGMS, Role in the project: Co-I
“Regulatory Roles of Cellular Cholesterol”
The primary aim of this project is to investigate the mechanisms underlying diverse cholesterol-mediated cell regulation. We will develop robust and versatile in situ quantitative imaging analysis of cellular cholesterol and determine how cholesterol regulates Wnt signaling through specific interaction with a scaffold protein, Dvl.
2016-2018 R13 Conference Grant (Levitan, lead PI, Rasgado-Flores, Blazer-Yost. Depielre, co-PIs)
“Cell Volume Regulation in Hydration and Nutrition”
2016-18 Postdoctoral AHA Fellowship (PI: Fancher)
American Heart Association (Sponsor: Levitan)
Epshtein, Y., Chopra, A., Rosenhouse-Dantsker, A. Kowalsky, G., Logothetis D.E. and I. Levitan. Identification of a C-terminus domain critical for the sensitivity of Kir2.1 channels to cholesterol. PNAS, 106(19):8055-60, 2009
Shentu TP, Singh DK, Oh MJ., Sun S, Sadaat L, Makino A, Mazzone T, Subbaiah PV, Cho M and I Levitan. The role of oxysterols in control of endothelial stiffness. Journal of Lipid Research, 53:1348-58, 2012. Featured in International Innovation Report.
Rosenhouse-Dantsker A, Noskov S, Durdagi S, Logothetis DE, Levitan I. Identification of novel cholesterol-binding regions in Kir2 channels. Journal of Biological Chemistry, 288(43):31154-64, 2013
Oh MJ, Zhang C, LeMaster E, Adamos C, Berdyshev E, Bogachkov Y, Kohler EE, Baruah J, Fang Y, Schraufnagel DE, Wary KK, Levitan I. Oxidized LDL signals through Rho-GTPase to induce endothelial cell stiffening and promote capillary formation. J Lipid Res. 57(5):791-808, 2016. Featured in Atlas of Science.
Ahn SJ, Fancher IS, Bian JT, Zhang CX, Schwab S, Gaffin R, Phillips SA, and I Levitan. Inwardly- rectifying K+ channels are major contributors to flow-induced vasodilation in resistance arteries. J of Physiology. 2016
Viswanathan Natarajan, PhD
1. P01 Hl077806-09 Malik (PI) 08/01/15-07/31/20 0.3 Cal M
Project 2 Sphingosine kinase 2 expression in macrophages promotes resolution of inflammatory lung injury
The goal of this project is to define the role of SphK2 in regulating TRPM2 channel in lung ECs to delineate its role in neutrophil-dependent increases in lung vascular permeability.
2. P01 HL126609 Garcia (PI)06/01/016 – 05/31/21 1.2 Cal M
Project 3: “Integrin β4 and Paxillin IN EC Focal adhesion Dynamics and Barrier Responses”
This project focuses on the role of integrin β4 and paxillin as targets for regulation of focal adhesions and barrier restoration in endothelium.
3. R01 HL127342-01 Roberto/Natarajan (MPI) 02/1/16 to 01/31/20 1.2 Cal M
Role of Sphingolipid Pathways in the pathobiology of Pulmonary Arterial Hypertension (PAH)
The goal of this application is to evaluate the sphingosine kinase 1/S1P signaling axis in pulmonary artery smooth muscle cells and development of PAH in the pulmonary artery.
Role: Multi PI
4. P01 HL060678 (PI, Malik, AB) 2/1/16 -2/28/21 2.4 Cal M Calendar
NIH/HLBI 1,726,178 (total cost/5 years)
Restoration of endothelial barrier integrity
Project 4: Phospholipase D2/SphK1 Signaling and Adherens Junction Assembly and Barrier Restoration
This project focuses on the spatiotemporal production of phosphatidic acid (PA) by PLD signaling and restoration of adherens junction and barrier integrity.
Role: Project Leader
Jiang, Y., Sverdlov, M.S., Toth, P.T., Du, G., Huang L., Liu, Y., Natarajan, V., and Minshall, R.D. RalA activation of PLD2-mediated phosphatidic acid production stimulates caveolae-mediated endocytosis and trafficking of endothelial cells. Journal of Biological Chemistry, 291; 20729-20738, 2016.
Black, K.E., Bain, G., Berdyshev, E., Castelino, F.V., Shea, B.S., Probst, C.K., Fontaine, B., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R.S., Natarajan, V., and Tager, A.M. Autotaxin activity increases following lung injury, but is not required for LPA production in the lung or for pulmonary fibrosis. FASEB J, 30: 2435-2450, 2016.
Harijith, A., Pendyala, S., Ebenezer, D., Ha, A., Fu, P., Ma, K., Toth, P., Berdyshev, E., Kanteti, P., and Natarajan, V. Hyperoxia- induced p47phox activation and ROS generation is mediated through S1P transporter Spns2, and S1P/S1P1&2 signaling axis in lung endothelium. Am J Physiol Lung Cell Mol Physiol, 311: L337-L351, 2016.
Ebenezer, D.L., Fu, P., Suryadeva, V., Natarajan, V. Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine1-phosphate (S1P) in acute lung injury: Role of S1P Lyase. Advances in Biological Regulation, S2212-4926 (16)30044-6. Doi: 10.1016/j.jbior.2016.09.007, 2016.
Fu, P., Ebenezer, D.L., Berdyshev, E.V., Bronova, I.A., Shaaya, M., Harijith, A., and Natarajan, V. Role of Sphingosine Kinase 1 and S1P Transporter Spns2 in HGF-mediated lamellipodia formation in lung endothelium. Journal of Biological Chemistry, 291: 27187-27203, 2016.
Sharmilee Nyenhuis, MD
Ongoing Research Support: NIH NHLBI K01 HL133370 Nyenhuis (PI)
“ACTION Intervention: Physical Activity in Minority Women with Asthma”
Goal: The proposed study will modify a validated community-based walking intervention specific to the needs of sedentary African American women with asthma and evaluate the impact of the intervention on physical activity and asthma specific indicators to reduce the burden of asthma in sedentary African American women.
PCORI Contract #AS-1307-05420 Krishnan (PI) 3/1/2014-5/31/2017
“Coordinated Healthcare Interventions to Address Childhood Asthma Gaps (CHICAGO)”
Goal: Test both provider- and patient-level interventions to improve clinically meaningful outcomes in a minority pediatric ED population with uncontrolled asthma
Role: Clinical Site PI
PCORI Contract CDRN #1306-04737 Mazzany (PI) 10/1/15-9/30/18
“Chicago Area Patient Centered Outcomes Research Network (CAPriCORN)”
Goal: Accelerate the implementation of innovative methods to transition healthcare systems into learning health systems that impact healthcare quality, health outcomes, and health equity.
Role: Asthma Cohort Working Group co-chair, UIC Site Adult Asthma Cohort lead and Patient Consumer Engagement Working Group member
- Cabana, M, Kunselman S, Nyenhuis SM and Wechsler M. “Researching asthma across the ages: Insights from the National Heart, Lung and Blood Institute’s Asthma Network” J Allergy Clin Immunol 2014;133:27-33. PMID: 24369796; PMCID: PMC3901784
- Nyenhuis SM, Krishnan JA. “Stepping Up Asthma Therapy in the Real World” Ann Am Thorac Soc 2015;12(6):789-90. PMID: 26075550; PMCID: in progress
- Martin MA, Press VG, Nyenhuis SM, Krishnan JA, Erwin K, Mosnaim G, Helen Margellos-Anast H, Paik SM, Ignoffo S, McDermott M, the CHICAGO Plan Consortium. Care transition interventions for children with asthma in the emergency department. Journal of Allergy and Clinical Immunology. 2016;138(6):1518-1525. PMID: 27931533
- Nyenhuis SM, Krishnan JA, Berry A, Calhoun WJ, Chinchilli VM, Engle L, Grossman N, Holguin F, Israel E, Kittles RA, Kraft M, Lazarus SC, Lehman EB, Mauger DT, Moy JN, Peters SP, Phipatanakul W, Smith LJ, Sumino K, Szefler SJ, Wechsler ME, Wenzel S, White SR, Ackerman SJ. “Race is Associated with Differences in Airway Inflammation in Asthma” Journal of Allergy and Clinical Immunology. Epub ahead of print 12/31/16.
- Corbridge SJ, Nyenhuis SM. Promoting Physical Activity and Exercise in Patients with Asthma and Chronic Obstructive Pulmonary Disease. Journal of Nurse Practitioners, 2017; 12 (1): 41-46.
Gye Young Park, MD
Current Support: NIH R01 1R01HL126852-01A1 (PI: Gye Young Park, 25% effort)
Role of alternatively activated macrophages in allergic asthma
3/1/16-12/31/20 3.1 cal months Annual direct costs $262,7290
The major goals of this project are to examine the details of the cellular and biochemical steps of inflammation in alveolar macrophage cells which are likely to be responsible for the chronic refractory asthma. The proposed study could lead to a better understanding of the pathogenesis of asthma, which will eventually improve management of asthma.
Respiratory Health Association Lung Cancer Research Award (PI: Gye Young Park, 5% effort)
Macrophage regulation of lung cancer progression
7/1/16-6/30/18 0.6 months Annual direct costs $62,500
The major goals of this proposed study will investigate a new approach of immunotherapy to transform tumor-associated macrophages (TAMs) into a new phenotype that is less favorable for tumor growth. In this proposed study, we want to examine a highly innovative hypothesis which could lead to the development of a new immunotherapy against lung cancer.
NIH PPG (PI: Asrar Malik, PhD) NIH P01 HL077806, Role: Co-I of Core B (3% effort)
Mechanisms of Resolution of Lung Injury 8/1/2015-7/31/2020 0.36 Cal Months
Core B annual direct cost $149,573
Major goals of the project are to utilize novel and rigorous approaches to lead to a new overall understanding of the signaling mechanisms responsible for resolving lung inflammatory injury and potential therapeutic strategies to accelerate and enhance the pro-resolution mechanisms and make lungs tolerant to injury.
Major goals of Core B are to provide PMNs isolated from mouse blood and bone marrow, lung endothelial and epithelial cells isolated from mice from mice, and human macrophages from bronchoalveolar fluid.
NIH R01 (PI – Marcelo Bonini) NIH 1R01 1AI131267-A1, Role: Co-I (5% of effort)
Macrophage redox state in sterilizing and injurious inflammation. 04/01/17 – 03/31/2022 0.6 cal month
This project will unravel a broad and fundamental mechanism of voltage regulated gene transcription in macrophages affecting the host’s immune response and the resolution of the inflammatory process.
Karpurapu M, Wang X, Deng J, Park H, Xiao L, Sadikot RT, Frey RS, Maus UA, Park GY, Scott EW, Christman JW. Functional PU.1 in macrophages has a pivotal role in NF-κB activation and neutrophilic lung inflammation during endotoxemia. Blood. 2011 Nov 10;118(19):5255-66.
Lee YG, Jeong JJ, Nyenhuis S, Berdyshev E, Chung S, Ranjan R, Karpurapu M, Deng J, Qian F, Kelly EA, Jarjour NN, Ackerman SJ, Natarajan V, Christman JW, Park GY. Recruited Alveolar Macrophages, in Response to Airway Epithelial-derived MCP-1/CCL2, Regulate Airway Inflammation and Remodeling in Allergic Asthma. Am J Respir Cell Mol Biol. 2014 Oct 31.
Park GY, Lee YG, Berdyshev E, Nyenhuis S, Du J, Fu P, Gorshkova IA, Li Y, Chung S, Karpurapu M, Deng J, Ranjan R, Xiao L, Jaffe HA, Corbridge SJ, Kelly EA, Jarjour NN, Chun J, Prestwich GD, Kaffe E, Ninou I, Aidinis V, Morris AJ, Smyth SS, Ackerman SJ, Natarajan V, Christman JW. Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir Crit Care Med. 2013 Oct 15;188(8):928-40.
Chung S, Ranjan R, Lee YG, Park GY, Karpurapu M, Deng J, Xiao L, Kim JY, Unterman TG, Christman JW. Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia. J Leukoc Biol. 2015 Feb;97(2):327-39..
Ranjan R, Lee YG, Karpurapu M, Syed MA, Chung S, Deng J, Jeong JJ, Zhao G, Xiao L, Sadikot RT, Weiss MJ, Christman JW, Park GY. p47phox and reactive oxygen species production modulate expression of microRNA-451 in macrophages. Free Radic Res. 2015 Jan;49(1):25-34.
Bharati Prasad, MD
Current Support: 1IK2CX001026-01 (Prasad) VA CSR&D
Targeted Treatment of Obstructive Sleep Apnea to Reduce Cardiovascular Disparity
Goals: To examine mechanisms of hypertension and effects of CPAP treatment on 24 hour blood pressure in Veterans with sleep apnea.
Prasad B, Radulovacki M, Olopade C, Herdegen JJ, Logan T, Carley DW. Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnea syndrome.Sleep. 2010; 33(7):982-9.
Prasad B, Carley DW, Krishnan JA, Weaver TE, Weaver FM. Effects of positive airway pressure treatment on clinical measures of hypertension and type 2 diabetes.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2012; 8(5):481-7.
Prasad B, Radulovacki MG, Carley DW. Proof of concept trial of dronabinol in obstructive sleep apnea.Frontiers in psychiatry. 2013; 4:1.
Garg N, Rolle AJ, Lee TA, Prasad B. Home-based diagnosis of obstructive sleep apnea in an urban population.
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2014; 10(8):879-85.
Prasad B, Usmani S, Steffen AD, Van Dongen HP, Pack FM, Strakovsky I, Staley B, Dinges D, Maislin G, Pack AI, Weaver TE. Short-Term Variability in Apnea-Hypopnea Index during Extended Home Portable Monitoring.
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2016; 12(6):855-63.
Israel Rubinstein, MD
Title: Intralipid: a novel frontline countermeasure for brodifacoum poisoning
Source: National Institutes of Health U01 NS083457-02 Period of Support: 09/01/13-08/31/18
Amount: $2,230,000 direct costs (Co-I)
Title: Mechanisms and translation of lipid resuscitation
Source: Department of Veterans Affairs Merit Review (1I01BX001514-01A1) Period of Support: 10/01/2012-09/30/2017
Amount: $650,000 direct costs (Co-PI)
Title: LAMb Request for Edstrom PULSE Environmental Monitoring System for Veterinary Medical Unit
Source: Department of Veterans Affairs Merit Review (1IS1BX003991-01) Period of Support: 01/24/2017
Amount: $71,060 direct costs (PI)
1. Sethi V, Rubinstein I, Kuzmis A, Kastrissiois H, Artwohl J, Önyüksel H.
Novel, biocompatible, disease modifying nanomedicine of VIP for rheumatoid arthritis. Molecular Pharmaceutics 10: 728-738, 2013.
2. Fettiplace MR, Ripper R, Lis K, Feinstein DL, Rubinstein I, Weinberg G.
Intraosseous lipid emulsion: An effective alternative to intravenous delivery in emergency situations. Critical Care Medicine 42: e157-160, 2014.
3. Fettiplace MR, Pichurko A, Ripper R, Lin B, Kowal K, Lis K, Schwartz D, Feinstein DL, Rubinstein I, Weinberg G. Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether β-cyclodextrin. Academic Emergency Medicine 22: 508-518, 2015.
4. R. Bawa, G. F. Audette and I. Rubinstein. (Editors): Handbook of Clinical Nanomedicine: Nanoparticles, Imaging, Therapy, and Clinical Applications, Pan Stanford Publishing, Singapore (2016) [ISBN
978-981-4669-20-7 (Hardcover), 978-981-4669-21-4 (eBook)]; Volume 1.
5. Feinstein DL, Brodsky S, Weinberg G, van Breeman R, Rubinstein I.
Brodifacoum poisoning: A clear and present danger to public health in the USA. Toxicology Letters 268:71-72, 2017.
Sunit Singla, MD
1 K08 HL140222 (PI) 08/01/2018-07/31/2023
Role of lung WWOX deficiency in vascular leak during lung injury
Total Funding (approx.): $870,860
Acute respiratory distress syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and is seriously debilitating for many survivors29. Specific ARDS therapies do not currently exist, and efforts to reduce its burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The cardinal, morbidity-producing feature of ARDS is non-cardiogenic pulmonary edema resulting from pulmonary vascular barrier disruption with consequent alveolar flooding, and respiratory failure. The conceptual underpinning for these events consists of cytoskeletal contraction of pulmonary endothelial cells (ECs) leading to the formation of paracellular gaps. Novel strategies which reduce the vascular permeability and lung edema of ARDS are desperately needed. The objective of this proposal is to determine the contribution of the tumor suppressor WWOX to the pathobiological processes associated with ARDS. The major goals are to 1) determine the significance of endothelial cell WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes endothelial barrier protection, and 3)establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.
Department of Defense (Site PI) 04/01/2020-03/31/2024
Cooling to Help Injured Lungs (CHILL) Phase 2b Randomized Control Trial of Therapeutic Hypothermia in Patients with ARDS
Total Costs: $395,170
The goal of this work is to perform a Phase IIb randomized clinical trial to study the potential benefit and safety of mild hypothermia in patients with ARDS using 28-day ventilator-free days and other clinical and laboratory surrogates for mortality. This Phase IIb study will generate the necessary information to determine whether and how to design a definitive Phase III clinical trial of therapeutic hypothermia to reduce mortality in patients with ARDS. This trial will compare mild hypothermia (34°-35°C) plus neuromuscular blockade vs. standard temperature management in patients with moderate to severe ARDS.
Zeng, Zhenguo; Chen, Weiguo; Moshensky, Alexander; Khan, Raheel; Crotty-Alexander, Laura; Ware, Lorraine B.; Aldaz, Marcelo; Jacobson, Jeffrey R.; Dudek, Steven M.; Natarajan, Vishwanathan; Machado, Roberto F.; Singla, Sunit. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Preprint: https://doi.org/10.1101/2020.07.13.200832
Singla, Sunit; Machado, Roberto F. Death of the Endothelium in Sepsis: Understanding the Crime Scene. Am J Respir Cell Mol Biol. 2018 Apr 25. Epub ahead of print. PMID: 29694793
Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F. Loss of Lung WWOX Expression Causes Neutrophilic Inflammation. AJP: Lung Cellular and Molecular Physiology. 2017 Mar 10. Epub ahead of print. PMID: 28283473
Singla, Sunit; Sysol, Justin; Dille, Benjamin; Chen, Jiwang; Machado, Roberto F. Hemin Causes Lung Microvascular Endothelial Barrier Dysfunction by Necroptotic Cell Death. American Journal of Respiratory Cell and Molecular Biology. American Journal of Respiratory Cell and Molecular Biology. 2017 Apr 19. Epub ahead of print. PMID: 28421813
Singla, Sunit; Zhou, Tong; Javaid, Kamran; Zhang, Wei; Ma, Shwu-Fan; Wade, Michael S.; Noth, Imre; Sweiss, Nadera J.; Garcia, Joe G.N.; Machado, Roberto F. Expression Profiling Elucidates A Molecular Gene Signature Which Identifies Pulmonary Hypertension In Sarcoidosis. Pulmonary Circulation. 2016 Dec; 6(4): 465–471. PMCID: PMC5210052
Singla, Sunit; Predescu, Dan; Bardita, Cristina; Wang, Minhua; Zhang, Jian; Balk, Robert A.; Predescu, Sanda. Pro-inflammatory endothelial cell dysfunction is associated with intersectin-1s down-regulation. Respir Res.12; 2011 Apr 12:46.PMID:21486462
Patel, Gourang P.; Grahe, Jaime Simon; Sperry, Mathew; Singla, Sunit; Elpern, Ellen; Lateef, Omar; Balk, Robert A. Efficacy and Safety of Dopamine versus Norepinephrine in the Management of Septic Shock. Shock. 2010 Apr;33(4):375-80.PMID:19851126