This proposal describes a five-year career development program designed to lead the PI to a career as an independent clinician scientist studying the intersection of medical critical illness, neuroimmunology, and vascular biology. 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. While the population impact of brain dysfunction after critical medical illness is similar to morbidity associated with stroke and is an area of growing scientific interest, few studies investigate the mechanism of these changes, and there is little scientific basis for the rational design of treatments. The applicant has found that in a mouse model of sepsis, systemic illness results in long lasting neuroinflammation with infiltration of inflammatory cells, changes in resident microglial gene expression, and blood brain barrier dysfunction. In this proposal, the applicant will investigate the role of an endogenous danger signal, the protein S100A8/A9, in sustaining neuroinflammation and blood brain barrier dysfunction in a mouse model of sepsis, and determine if blockade of S100A8/A9 signaling ameliorates these effects. He will study the role of S100A8/A9 both in an in vitro model system and in vivo using a combination of pharmacologic and genetic approaches. These questions will also be extended to post mortem studies of neuropathology and gene expression in the brains of patients with sepsis. Applicant: The applicant holds M.D. and Ph.D. degrees and has completed specialty training in Internal Medicine and Pulmonary and Critical Care Medicine. He has previous experience in neuroscience research and using mouse models to study normal brain physiology and disease. The career development plan includes a period of mentored research aimed at developing new knowledge in both immunology and vascular biology that will greatly enhance his existing training and allow him to develop as an independent investigator in studying an intrinsically interdisciplinary problem in translational neuroscience. The training will include learning research techniques and acquiring scientific knowledge in the laboratories of and through meetings with the mentors and key collaborators, as well as didactic training, seminars, lab meetings, topic focused working groups, and national meetings. The training plan includes didactic training in grant writing and responsible conduct of research. The research environment provides intellectual interaction with investigators from neuroscience, immunology and vascular biology, as well as basic and clinical/translational scientists. Technology for advanced imaging, gene expression, and immunophenotyping is available. These opportunities will allow the applicant to be guided in developing both powerful investigative techniques and the intellectual tools for an independent career in a clinically important but underserved field of study.
Every year, over 1.3 million patients in the United States survive a hospitalization for sepsis. Over one third of these survivors will experience long lasting, significant brain dysfunction. The goal of this project is to understand the mechanism of these changes, which are unknown, in order to develop treatments.
|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|