Friday, April 26, 2024
4/26/2024
¿ DESCRIPTION (provided by applicant): This application for research training via the K08 mechanism originates from a trauma surgeon and critical care specialist that has been an assistant professor for three years. He now proposes a multi-dimensional training program intended to launch his academic career as a basic and translational surgeon-scientist and focused on one of the most pervasive problems in trauma and critical care medicine, specifically, multiple organ system failure (MOSF). The training program - physically located in the highly interdisciplinary and well-funded Center for Lung Biology and in the region's only level 1 Trauma Center - is intended to provide the candidate with (1) core knowledge and laboratory skills, (2) state-of-the-art expertise in research methods and biostatistics, and (3) scientific writing, presentation, and academic leadership skills. A combination of didactic courses, judicious attendance at on-site and off-site seminars and meetings, and intense laboratory experiences will be utilized to achieve these goals. The proposed research plan is motivated by two striking gaps in the care of patients with MOSF. First, although outcomes of severe injury have improved partly as a consequence of advances in resuscitation and supportive care, MOSF remains a serious clinical problem because pharmacologic strategies to prevent or reverse the syndrome have yet to be developed. Second, while mitochondrial and bioenergetic dysfunction have long been incriminated in the response to severe injury, the prospect that key sentinel molecule(s) integrating cellular responses to systemic inflammation reside in these mitochondrial and bioenergetic abnormalities has not previously been considered. Accordingly, the candidate's research training plan will test the novel concept that mitochondrial DNA (mtDNA) acts as a molecular sentinel governing deleterious cell responses in MOSF. Multiple lines of evidence converge on this idea. The mitochondrial genome is far more sensitive to oxidative damage than nuclear DNA, an observation whose significance is underscored by involvement of reactive species of oxygen and nitrogen (RS) across the spectrum of MOSF. Further, modulation of mtDNA repair efficiency using transgenic strategies or novel platform drugs coordinately dictate survival and function in oxidant or bacteria-challenged cultured cells, isolated organs, and intact animals. Most provocatively, recent evidence incriminates mtDNA as an intercellular mediator of MOSF. Fragments of the mitochondrial genome released into the circulation after injury - termed mtDNA Damage Associated Molecular Patterns (DAMPs) - may serve to propagate damage from the initial site of injury to distant organs through TLR-mediated activation of inflammatory and resident cells (19). Because molecular determinants of mtDNA DAMP disposition are entirely unexplored, the proposed research will test the translationally-significant hypothesis that in severe trauma, oxidative base damage to the mitochondrial genome causes plasma accumulation of mtDNA DAMPs resulting in the evolution of MOSF. Studies in severely injured human patients, human peripheral blood mononuclear cells (PBMCs), and in a rodent model of MOSF will: (1) Define relationships between plasma mtDNA DAMP levels and indices of MOSF in patients with severe trauma; (2) Test the hypothesis in human PBMCs that oxidant- mediated mtDNA damage and mtDNA repair kinetics are positively and negatively, respectively, associated with mtDNA DAMP release into the extracellular environment; and, (3) Determine if increased mtDNA repair and enhanced mtDNA DAMP degradation with novel platform drugs, prevents and reverses MOSF In a rat model of Pseudomonas aeruginosa-induced sepsis. Collectively, this research will provide the first observational evidence linking plasma mtDNA DAMPs to the evolution of MOSF in a vulnerable population of severely injured patients. However, its most innovative and significant contributions relate to the identification of isolated targets for pharmacologic intervention in MOSF by providing proof-of-concept that strategies to augment mtDNA repair and accelerate mtDNA DAMP degradation suppress mtDNA DAMP accumulation and propagation of organ failure. It is believed that at the end of this training program, the candidate will be well positined to launch the first clinical trials on strategies to control mtDNA DAMP- mediated MOSF in severe injury. In addition, the candidate will inaugurate an independent laboratory research program whose goal will be define at a molecular level novel pharmacologic targets to govern mtDNA DAMP disposition in trauma and other disorders for which these inter- and intracellular mediators play pathogenic role.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
