2005 — 2009 |
Saito, Hiroshi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vulnerability to Sepsis in Old Age
DESCRIPTION (provided by applicant): Sepsis is an infection-initiated manifestation of the systemic inflammatory response syndrome that often progresses to septic shock, multiple organ failure with high risks of death. Sepsis is a particularly serious problem in the geriatric population, as the elderly patients with sepsis suffer much higher morbidity and mortality than younger patients. In fact, sepsis is a major cause of death in elderly patients at intensive care units in the US. Although this problem is increasingly recognized, the underlying mechanism(s) responsible for this age-associated vulnerability remain largely unknown. The long-term goal of our research is to determine the mechanisms responsible for the increased septic vulnerability in the aged, and to use this information to develop new treatment strategies for sepsis. The age-associated vulnerability to sepsis is also seen in animal models. We have shown that aged mice suffer significantly higher mortality than young mice in two commonly used models for sepsis;endotoxemia induced by bacterial lipopolysaccharide injection, and an intra-abdominal sepsis induced by cecal ligation and puncture. We have also found that the elevated mortality in aged mice is associated with altered inflammatory and coagulation responses, and increased oxidative damages. Our central hypothesis is that loss of homeostasis in old age leads to excessive inflammation, oxidative damage, and coagulation, contributing to the age-associated vulnerability to sepsis. Our objective in this project is to define the age-associated alterations in pathophysiology and gene expression in the mouse model of sepsis, and to develop strategies to improve the survival of the old mice with sepsis. To achieve these goals, we pursue the following three specific aims: (1) To determine the effects of aging on the pathophysiology of sepsis, (2) To identify the age-associated alterations in gene expression that affects mortality in sepsis, and (3) To test likely strategies for their ability to decrease age-associated mortality in sepsis. The information obtained from this project should provide the basis for new therapeutic strategies to substantially decrease the mortality in elderly patients with sepsis.
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0.984 |
2011 — 2015 |
Saito, Hiroshi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Adipose Tissue in Age-Dependent Sensitivity to Critical Illness
DESCRIPTION (provided by applicant): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins, including cytokines, coagulation factors and hormones, may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals, we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.
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0.961 |
2017 — 2020 |
Saito, Hiroshi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chronic Muscle Weakness in Sepsis Survivors
ABSTRACT The objective of this project is to identify sub-cellular and molecular mechanisms of skeletal muscle dysfunction that are responsible for chronic weakness in sepsis survivors. Using the knowledge obtained, this project will elucidate potential therapeutic interventions targeting post-sepsis chronic muscle weakness. Over 1 million sepsis survivors are now discharged from the hospital every year, and a majority of these survivors report reduced quality of life due to considerable muscle weakness lasting for years after hospital discharge. However, the lack of an appropriate animal model has been a critical barrier to identifying the changes which persist long after recovery from sepsis. We recently developed a new mouse model that has enabled us to evaluate long-term muscle quality and function in severe sepsis survivors. Our preliminary studies demonstrate that sepsis-surviving mice exhibit significant skeletal muscle weakness, even after bacterial infection and inflammation are resolved and muscle mass is recovered, giving us the unique opportunity to evaluate molecular mechanisms of muscle weakness beyond the muscle wasting phenotype. Skeletal muscles from these sepsis-surviving mice also show histological abnormalities, significant nitro-oxidative damage, and profound structural and functional defects in mitochondria. These preliminary results support our central hypothesis that sepsis-induced oxidative damage causes mitochondrial dysfunction and sarcomeric protein damage, both of which remain long after sepsis recovery, and these are the major contributors to the sustained skeletal muscle weakness in sepsis survivors. Specific Aims to test the hypothesis are: (1) To determine mitochondrial damage and dysfunction in sepsis-surviving mice; (2) To investigate sarcomeric protein damage and its causal mechanisms in sepsis-surviving mice; and (3) To formulate therapeutic strategies to ameliorate post-sepsis chronic muscle weakness.
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0.961 |
2017 — 2021 |
Saito, Hiroshi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms Mediating Severity of Acute Pancreatitis in the Aged
ABSTRACT The objective of this project is to understand the mechanisms leading to the development of severe acute pancreatitis (sAP), a life-threatening illness with high mortality characterized by necrotizing pancreas, severe systemic inflammation, coagulation, multiple organ dysfunction syndrome (MODS). AP is a particularly serious disease among the elderly as both incidence and the likelihood for progression to sAP increases dramatically with advancing age. Despite recognition of this clinical problem, little is known regarding the underlying biological mechanisms of this disease or why progression to sAP is more common among elderly patients. We recently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinical observations including prolonged systemic inflammation, coagulation, MODS, and fatality. Our observations with this mouse model include a dramatic age-dependent increase in tissue damage and cytokine gene expression within visceral adipose tissue, and elevated levels of free fatty acids in the ascitic fluid. Collectively these findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAP in the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due to pronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymes into the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release of free fatty acids, inflammatory cytokines, and pro-thrombotic factors, all promoting MODS. Our hypothesis will be tested in the following three specific aims: To determine features of visceral adipose tissue inflammation in aged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotes the progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of AP to sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).
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0.961 |