Our overall goal is to elucidate the physiologic, genetic, and molecular aspects of two common co-morbid conditions, asthma and nocturnal oxygen desaturation, that increase the incidence rate of pain in sickle cell anemia (SCA). In separate studies, we have shown children with SCA and either asthma or nocturnal desaturation have an increased pajn rate when compared to children without the condition. Also, our group demonstrated that in a murine model of SCA there was significant susceptibility to hypoxia-induced pulmonary vasocongestion when compared to mice without SCA. Unfortunately, we do not know the interrelationship if any, between asthma, nocturnal desaturation and lung disease in SCA. We propose three interrelated projects. The first and second clinical projects will delineate the physiological basis for the association of asthma and nocturnal desaturation with SCA related morbidity. The first project will also obtain DMA and clinical information from 1800 children with SCA participating in the Silent Cerebral Infarct (SIT) Trial. We will perform a case-control study evaluating whether genes associated with asthma increase the risk of pain and ACS episodes. The basic science project will have experiments aimed at defining the molecular mechanisms by which asthma and nocturnal hypoxemia, separately and together, increase lung injury in a transgenic SCA murine model. We will test three global hypotheses: 1) phenotypic and genotypic features of asthma are risk factors for pain and ACS episodes in children with SCA; 2) nocturnal desaturation in children with SCA modifies the effect of asthma on morbidity in SCA; and 3) chronic airway inflammation and nocturnal hypoxia, separately and together, increase HbSS-induced lung injury in a murine SCA model. Taken together, the results of this highly interactive collaboration of clinical and basic scientists will permit new insights into the mechanisms of lung disease, thus providing a strong foundation for targeted therapy for this vulnerable group.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079937-04
Application #
7457787
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Blaisdell, Carol J
Project Start
2005-08-25
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$1,841,516
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Willen, Shaina M; Cohen, Robyn; Rodeghier, Mark et al. (2018) Age is a predictor of a small decrease in lung function in children with sickle cell anemia. Am J Hematol 93:408-415
Willen, Shaina M; Rodeghier, Mark; Strunk, Robert C et al. (2018) Aeroallergen sensitization predicts acute chest syndrome in children with sickle cell anaemia. Br J Haematol 180:571-577
Willen, Shaina M; Rodeghier, Mark; Rosen, Carol L et al. (2018) Sleep disordered breathing does not predict acute severe pain episodes in children with sickle cell anemia. Am J Hematol 93:478-485
Willen, Shaina M; Rodeghier, Mark; Strunk, Robert C et al. (2017) Airway Hyperresponsiveness Does Not Predict Morbidity in Children with Sickle Cell Anemia. Am J Respir Crit Care Med 195:1533-1534
Cohen, Robyn T; Rodeghier, Mark; DeBaun, Michael R (2017) Reply: Decline of Lung Function in Children with Sickle Cell Disease Is Not Associated with Restrictive Defects. Ann Am Thorac Soc 14:478
Cohen, Robyn T; Rodeghier, Mark; Kirkham, Fenella J et al. (2016) Exhaled nitric oxide: Not associated with asthma, symptoms, or spirometry in children with sickle cell anemia. J Allergy Clin Immunol 138:1338-1343.e4
DeBaun, Michael R; Strunk, Robert C (2016) The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia. Lancet 387:2545-53
McClain, Brandi L; Ivy, Zalaya K; Bryant, Valencia et al. (2016) Improved Guideline Adherence With Integrated Sickle Cell Disease and Asthma Care. Am J Prev Med 51:S62-8
Cohen, Robyn T; Strunk, Robert C; Rodeghier, Mark et al. (2016) Pattern of Lung Function Is Not Associated with Prior or Future Morbidity in Children with Sickle Cell Anemia. Ann Am Thorac Soc 13:1314-23
Karafin, Matthew S; Dogra, Shibani; Rodeghier, Mark et al. (2016) Increased circulating fibrocytes are associated with higher reticulocyte percent in children with sickle cell anemia. Pediatr Pulmonol 51:295-9

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