This project is a component of the Lung Inflammatory Disease program of the Programs of Excellence in Glycosciences (LID-PEG). In this project we seel< to develop leukocyte targeted nanoparticles bearing glycan ligands of siglecs, and investigate their use in diagnosis and therapy of lung and cardiovascular diseases. The siglecs are a family of immune receptors that bind sialic acid containing glycans as ligands. Most siglecs are expressed on leukocytes and are well documented as regulators of cell signaling in innate and adaptive immunity. Because each siglec is expressed on one or a few cell types, they are well suited as targets for cell directed therapies for diseases caused by leukocytes. The applicant's laboratory has developed nanoparticle platforms decorated with siglec ligands that are capable of selectively targeting and delivering cargo to cells expressing the corresponding siglec. In the proposed project we will use these nanoparticles to target leukocytes that play critical roles in the initiation and progression of lung and cardiovascular disease. Nanoparticles decorated with ligands to Siglec-8 (murine Siglec-F) will be used to target eosinophils, Siglec-9 (murine Siglec-E) to target neutrophils, and sialoadhesin (Sn; Siglec-1) to target monocytes/macrophages. Nanoparticles targeting each leukocyte cell type will be tested for their activity in murine models of allergic asthma and chronic obstructive pulmonary disease (COPD), and sialoadhesin (macrophage) targeted nanoparticles will be tested for diagnosis and amelioration of atherosclerotic plaque in a murine model of atherosclerosis. The results will help establish the roles of the corresponding cell types in disease processes, and document the potential utility of siglec- targeted nanoparticles in the diagnosis and treatment of lung and cardiovascular disease.

Public Health Relevance

This project seeks to develop novel cell targeted nanoparticles that can deliver agents to white blood cells for diagnosis and treatment of lung and cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107151-07
Application #
9277539
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Program Officer
Caler, Elisabet V
Project Start
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
7
Fiscal Year
2017
Total Cost
$491,600
Indirect Cost
$1,913
Name
Johns Hopkins University
Department
Type
Domestic Higher Education
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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O'Sullivan, Jeremy A; Carroll, Daniela J; Cao, Yun et al. (2018) Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e7
O'Sullivan, Jeremy A; Wei, Yadong; Carroll, Daniela J et al. (2018) Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils. J Leukoc Biol 104:11-19
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Chen, Zi; Bai, Fang-Fang; Han, Lu et al. (2018) Targeting Neutrophils in Severe Asthma via Siglec-9. Int Arch Allergy Immunol 175:5-15
O'Sullivan, Jeremy A; Bochner, Bruce S (2018) Eosinophils and eosinophil-associated diseases: An update. J Allergy Clin Immunol 141:505-517
Bochner, Bruce S (2018) The eosinophil: For better or worse, in sickness and in health. Ann Allergy Asthma Immunol 121:150-155
Gonzalez-Gil, Anabel; Porell, Ryan N; Fernandes, Steve M et al. (2018) Sialylated keratan sulfate proteoglycans are Siglec-8 ligands in human airways. Glycobiology 28:786-801
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83

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