Severe sepsis annually affects over 750,000 people in the US, and more than a third die, primarily due to multiple organ dysfunction (MOD). Though the last decade has seen immense progress in identifying the cellular and molecular mechanisms of MOD, major gaps in our knowledge still remain. Recent studies propose that the initial `organ dysfunction' is due to a regulated induction of a hypometabolic state, the purpose of which is cellular protection. However a delicate balance is required. Insufficient induction, as is observed in aging, may lead to irrecoverable cellular injury and organ dysfunction. On the other hand, with prolonged or overly severe insult, this mechanism of cytoprotection may actually contribute to organ injury. The ability to titrate this response may provide an opportunit to reverse MOD. Our lab seeks to delineate the biological determinants of organ dysfunction during sepsis. We have focused upon calcium (Ca2+) regulation and signaling to show that a family of Ca2+/calmodulin-dependent protein kinases (CaMK) regulate autophagy, a conserved cytoprotective response that enables a cell to recycle cytoplasmic components to adapt to periods of stress. However, Ca2+ signaling is inherently sensitive to the energy status of the cell, and mitochondria, the primary source of aerobic energy, both regulate and are regulated by Ca2+. We now hypothesize that sepsis induces CaMK signaling, which regulates adaptive changes in mitochondrial function to limit cellular injury. These mechanisms are altered during the aging process, which may underlie an increased risk of irreversible organ failure and death. We propose that early during sepsis the CaMK control adaptive changes in mitochondrial function and induce a hypometabolic, hibernating state, the purpose of which is to protect the cell. Severe sepsis perturbs mitochondrial function, leading to mitochondrial depolarization, the inciting event activating the CaMK. These CaMK mark damaged mitochondria for CaMK-dependent mitophagy (i.e. controlled cellular degradation of mitochondria). Concomitantly, the CaMK initiate mitochondrial biogenesis that restores a healthy mitochondrial population, aerobic metabolism, and organ function. Altered expression of these mechanisms occurs during the aging process, which underlies an increased risk of organ dysfunction. In accordance with our hypothesis we propose the following specific aims:
Specific Aim 1. To determine that intracellular and mitochondrial Ca2+ signaling activate the family of CaMK to regulate adaptive reductions in mitochondrial respiration and function during sepsis.
Specific Aim 2. To determine that mitochondrial Ca2+ signaling selectively targets dysfunctional mitochondria for CaMK-dependent mitophagy and induces CaMK-dependent mitochondrial biogenesis during sepsis. These mechanisms mitigate cellular injury and foster organ recovery.
Specific Aim 3. To determine that during aging, a progressive loss in CaMK signaling underlies an attenuation in mitophagy and mitochondrial biogenesis and an increased risk of organ dysfunction during sepsis. These investigations are highly innovative and based upon strong preliminary data. Understanding the mechanisms of a reversible cause of organ dysfunction will enable us to identify high-risk populations (i.e. elderly) and develop therapies to foster recovery even in the setting of established organ dysfunction.

Public Health Relevance

The development of sepsis from infection is a leading cause of death worldwide. The development of multiple organ dysfunction (MOD) secondary to sepsis accounts for nearly all of these deaths. Though the last decade has seen immense progress in identifying the mechanisms of MOD, major gaps in our knowledge still remain. Recent studies propose that the initial `organ dysfunction' is due to a regulated induction of a hypometabolic state, the purpose of which is cellular protection. Our data suggest that early during severe sepsis, calcium (Ca2+) signaling through a family of Ca2+/calmodulin-dependent protein kinases (CaMK) regulates adaptive changes in mitochondrial function to limit cellular injury. We further show that a delicate balance is required, as insufficient induction of these mechanisms, which is observed in aging, may lead to irrecoverable cellular injury and organ dysfunction. On the other hand, with prolonged or overly severe insult, this mechanism of cytoprotection may actually contribute to organ injury. The ability to titrate these responses may provide an opportunity to reverse MOD.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082852-09
Application #
9407788
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2009-08-03
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2020-01-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lewis, Anthony J; Griepentrog, John E; Zhang, Xianghong et al. (2018) Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial. Crit Care Med 46:e426-e434
Lewis, Anthony J; Zhang, Xianghong; Griepentrog, John E et al. (2018) Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis. Crit Care Med 46:e779-e787
Lewis, Anthony J; Lee, Janet S; Rosengart, Matthew R (2018) Translational Sepsis Research: Spanning the Divide. Crit Care Med 46:1497-1505
Zhang, Xianghong; Yuan, Du; Sun, Qian et al. (2017) Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis. FASEB J 31:4382-4395
Lewis, Anthony; Zuckerbraun, Brian; Griepentrog, John et al. (2017) Reducing Animal Use with a Biotelemetry-Enhanced Murine Model of Sepsis. Sci Rep 7:6622
Lewis, Anthony J; Yuan, Du; Zhang, Xianghong et al. (2016) Use of Biotelemetry to Define Physiology-Based Deterioration Thresholds in a Murine Cecal Ligation and Puncture Model of Sepsis. Crit Care Med 44:e420-31
Lewis, Anthony J; Billiar, Timothy R; Rosengart, Matthew R (2016) Biology and Metabolism of Sepsis: Innate Immunity, Bioenergetics, and Autophagy. Surg Infect (Larchmt) 17:286-93
Yuan, Du; Collage, Richard D; Huang, Hai et al. (2016) Blue light reduces organ injury from ischemia and reperfusion. Proc Natl Acad Sci U S A 113:5239-44
Zhang, Xianghong; Howell, Gina M; Guo, Lanping et al. (2014) CaMKIV-dependent preservation of mTOR expression is required for autophagy during lipopolysaccharide-induced inflammation and acute kidney injury. J Immunol 193:2405-15
Zhao, Y; Xiong, Z; Lechner, E J et al. (2014) Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury. Mucosal Immunol 7:440-8

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