In the US, sepsis affects more than 750,000 people annually, with a mortality rate as high as 30%. There is still no effective therapy for patients wih sepsis and septic shock. Excessive neutrophil infiltration is a major determinant of organ injury in sepsis, suggesting that targeting neutrophil trafficking is a rational strategy to reduce sepsis morbidity and mortality. The interaction between neutrophils and activated endothelial cells (ECs) is a key regulator of neutrophil infiltration. We have discovered that milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is able to reduce the number of neutrophils in organs of septic animals. Administration of recombinant human MFG-E8 after sepsis not only attenuated organ damage, but also doubled the survival of septic animals. We have also discovered that cold-inducible RNA-binding protein (CIRP) is released into the circulation in sepsis and functions as a damage-associated molecular pattern (DAMP). We have demonstrated that blocking CIRP activities with CIRP-neutralizing antibodies after sepsis not only inhibited inflammation, but also markedly improved the survival of septic animals. Recently, we have demonstrated that injection of recombinant murine CIRP into healthy mice caused EC activation and vascular leakage in the lungs. One focus of this proposal is to further elucidate the mechanisms responsible for MFG-E8's regulation of neutrophil trafficking and CIRP's control of EC activation. These findings will guide the design and development of new therapeutics for treating sepsis. Due to the complexity and difficulty in developing protein-based biotherapeutics, we focused on identifying small molecule-like oligopeptides derived from MFG-E8 and CIRP. To date, we have identified two candidate peptides, MSP68 and C23, derived from MFG-E8 and CIRP, respectively. We will further evaluate their efficacy, half-life and toxicity for treating sepsis. In this research program, we will address the following three key questions: 1) How does MFG-E8 inhibit neutrophil activation and infiltration in sepsis? 2) How does CIRP cause vascular EC activation and injury in sepsis? 3) Can we develop an anti-sepsis strategy targeting the neutrophil-EC interaction? The proposed research will lead to a new direction for the development of innovative therapeutics to treat patients suffering from sepsis and septic shock.

Public Health Relevance

Sepsis is a strong and deadly inflammatory response to germs in the circulation. Sepsis is one of the top ten leading causes of death in the US. Every year, sepsis affects more than 750,000 and kills more than 210,000 Americans, which is more than the four deadliest cancers combined. Additionally, sepsis costs $16.7 billion per year in health care expenditure. No effective anti-sepsis drug has been found. Thus, there is an urgent need for an effective anti-sepsis treatment. Our innovative and pioneering research led to the discovery of A) MFG-E8 as a molecule that protects organs from the invasion of damage-causing white blood cells, and of B) CIRP, a protein released during sepsis that increases inflammation by acting on white blood cells and the cells lining the blood vessels. Based on these molecules, we have generated two new anti-sepsis agents: MSP68 and C23. Research supported by this grant will improve our understanding of how to stop white blood cells from migrating to and damaging organs during sepsis, how to prevent CIRP from activating the blood vessel-lining cells and further increasing inflammation, and eventually develop two new therapeutic agents to effectively treat septic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118337-02
Application #
9270556
Study Section
Special Emphasis Panel (ZGM1-TRN-5 (MR))
Program Officer
Dunsmore, Sarah
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$460,636
Indirect Cost
$187,261
Name
Feinstein Institute for Medical Research
Department
Type
Research Institutes
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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Hansen, Laura W; Jacob, Asha; Yang, Weng Lang et al. (2017) Deficiency of receptor-interacting protein kinase 3 (RIPK3) attenuates inflammation and organ injury in neonatal sepsis. J Pediatr Surg :
Hendricks, Louie; Aziz, Monowar; Yang, Weng-Lang et al. (2017) Milk fat globule-epidermal growth factor-factor VIII-derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1. J Surg Res 208:10-19
Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang et al. (2017) Milk fat globule-epidermal growth factor-factor VIII attenuates sepsis-induced acute kidney injury. J Surg Res 213:281-289
Hansen, Laura W; Yang, Weng Lang; Bolognese, Alexandra C et al. (2017) Treatment with milk fat globule epidermal growth factor-factor 8 (MFG-E8) reduces inflammation and lung injury in neonatal sepsis. Surgery 162:349-357
Hansen, Laura W; Khader, Adam; Yang, Weng-Lang et al. (2017) Deficiency in milk fat globule-epidermal growth factor-factor 8 exacerbates organ injury and mortality in neonatal sepsis. J Pediatr Surg 52:1520-1527
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Khan, Mohammad Moshahid; Yang, Weng-Lang; Brenner, Max et al. (2017) Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Sci Rep 7:41363
Cen, Cindy; Aziz, Monowar; Yang, Weng-Lang et al. (2017) Osteopontin Blockade Attenuates Renal Injury After Ischemia Reperfusion by Inhibiting NK Cell Infiltration. Shock 47:52-60
Matsuo, Shingo; Sharma, Archna; Wang, Ping et al. (2017) PYR-41, A Ubiquitin-Activating Enzyme E1 Inhibitor, Attenuates Lung Injury in Sepsis. Shock :

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