This proposal describes a supplement to a career development award. The underlying career development program is designed to lead the PI to a career as an independent clinician scientist studying the intersection of medical critical illness, neuroimmunology, and vascular biology. The supplemental funds will support applying the findings of the underlying award to model mechanisms of cognitive decline associated with systemic illness in Alzheimer?s disease. The proposed pilot experiments will provide critical preliminary data for an R01 proposal examining the interaction of neuroinflammatory priming that results from amyloid deposition and the neuroinflammatory response to sepsis, thus supporting the applicant?s career development and transition to independence. Research plan: Long term brain dysfunction, including cognitive and affective disorders, is common among the 1.3 million patients who survive critical illness every year in the United States. Hospitalization is associated with increased risk of incident dementia among older adults, and patients with underlying Alzheimer?s disease neuropathology are particularly vulnerable to long-lasting cognitive effects of acute illness. The applicant has found that in a mouse model of sepsis, systemic illness results in long-lasting neuroinflammation including infiltration of inflammatory cells, priming of microglial reactivity, and astrocyte activation which accompany deficits in affective behavior. These changes are driven in part by an endogenous danger signal, the protein S100A8/A9, which signals via the receptor TLR4. In patients who die of sepsis, brain expression of neuroinflammatory markers is related both to underlying sepsis and to neurodegenerative disease. The central hypothesis of this proposal is that ?-amyloid deposition in the brain increases vulnerability to the effects of sepsis survival and acts synergistically with the insults of sepsis to amplify persistent neuroinflammation after sepsis. In this pilot study, this hypothesis will be tested by examining hippocampal-dependent learning and memory, molecular markers of inflammation, microglial priming, and leukocyte infiltration in both wild-type and ?-amyloid overexpressing mice, and testing the role of TLR4 signaling in these changes. Applicant: The applicant holds M.D. and Ph.D. degrees, has completed specialty training in Internal Medicine and Pulmonary and Critical Care Medicine, and is currently conducting mentored research. The pilot studies proposed here will allow the applicant to apply insights, models, and techniques developed during the period of mentored research to the study of Alzheimer?s disease. These studies will thus support the applicant?s transition to independence while also generating new insights into potentially reversible mechanisms of cognitive decline in patients suffering from neurodegenerative disease.
Every year, over 1.3 million patients in the United States survive a hospitalization for sepsis and over one third of these survivors will experience long lasting, significant brain dysfunction. Hospitalization may result in significant and precipitous functional decline for patients with early, often asymptomatic Alzheimer?s disease. The goal of this project is to understand whether the pathology of Alzheimer?s disease potentiates chronic neuroinflammatory responses in sepsis survivors.
| Denstaedt, Scott J; Spencer-Segal, Joanna L; Newstead, Michael W et al. (2018) S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis. J Immunol 200:3188-3200 |
| Singer, Benjamin H; Dickson, Robert P; Denstaedt, Scott J et al. (2018) Bacterial Dissemination to the Brain in Sepsis. Am J Respir Crit Care Med 197:747-756 |
| Denstaedt, Scott J; Singer, Benjamin H; Standiford, Theodore J (2018) Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation. Front Immunol 9:2446 |
