TRAINING & CAREERS
2018 BESIP Project
Laboratory and Project Description
The Extremity Trauma & Amputation Center of Excellence (EACE) is a one of a kind organization within the Department of Defense and Department of Veterans Affairs consisting of teams of researchers embedded at the point of care within multiple Military Treatment Facilities (MTFs) across the nation. In line with the congressionally directed mission of the EACE, the research efforts undertaken focus on the mitigation, treatment and rehabilitation of traumatic extremity injuries and amputations with a specific focus on translating their findings into clinical practice to improve the care of SMs and Veterans. The proposed preclinical work will be conducted by the EACE-Bethesda team at both Walter Reed National Military Medical Center (WRNMMC), the nation's largest and most renowned military medical center, and The Uniformed Services University of the Health Sciences (USUHS), the Nation's Federal health sciences university which is committed to excellence in military medicine and public health during peace and war. These world class institutions offer a full suite of infrastructure and facilities which are ideally suited for a wide variety of research activities (i.e., bench to bedside). Importantly, the EACE-Bethesda multidisciplinary team is comprised of basic and translational scientists of varying educational background, and clinicians from across the medical spectrum, which when taken together, provides a privileged perspective of the injury conditions that challenge wounded SMs. Furthermore, due to the aforementioned team, infrastructure, and facilities, subsequent clinical studies can be quickly initiated and conducted, if/when preclinical finding support further translation
The battle mortality rate for US forces has decreased from 30% in WWII to less than 10% in the OIF/OEF conflicts. However, the decreased mortality rate has been accompanied by an increase in the percentage and absolute number of seriously injured soldiers. These soldiers survive but are left with extraordinary, life affecting injuries; especially complex and severe extremity injuries. Indeed, extremity wounds make up the most common survivable injuries of modern military conflict and comprise two-thirds of initial hospital costs to the DoD. Owing to the unrelenting resolve and dedication of the SMs, their families, and the numerous members of the multi-disciplinary care teams, both active duty and civilian, significant advances in the care of SMs with combat-related extremity trauma has achieved over the past nearly two decades of conflict. The MTFs have led the way in advancing the standard of care for patients with severely traumatized salvaged limbs. The utilization of a team approach and state-of-the-art technologies within these institutions, has produced salient advancements in returning injured SMs and veterans to the highest level of function and QoL. However, outcomes can differ among these individuals; thus, additional research is needed to develop the next generation of technologies and approaches which will be required to realize true clinical success. Specifically, the demand for a regenerative medicine (RM) therapeutics and/or tissue engineering approaches which can restore full function and quality of life following traumatic extremity injury is extremely high.
One such RM therapeutic, extracellular matrix based biologic scaffolds, have been utilized extensively to improve the host response to injury by shifting the response away from an inflammatory, fibrotic response and towards a regenerative response. A wide variety of biologic scaffolds are used clinically for the repair and reinforcement of numerous tissues and organs. Despite a large cohort of clinical data showing beneficial results, occasionally these biologic scaffold materials fail to induce or only partially induce a beneficial remodeling response. Minimizing this variability requires an intimate knowledge of the molecular and cellular processes that biologic scaffolds initiate during the remodeling process. Unfortunately, to date, the mechanism(s) by which biologic scaffolds promote constructive remodeling are not completely understood. However, modulation of the host innate immune response - and more specifically, macrophages - toward a regulatory and constructive phenotype has been shown to be critically important. Macrophages have been shown to occupy a wide array of interchangeable phenotypes spanning the classic pro-inflammatory phenotype (M1) at one extreme to the regulatory, anti-inflammatory phenotype (M2) at the other. Numerous reports have indicated that biologic scaffolds promote an M2 macrophage phenotype during the tissue remodeling cascade. Strikingly, both the development of an M2 phenotype and the remodeling of injured skeletal muscle are strongly influenced by the soluble factors that are synthesized by Cyclooxygenase 2 (COX2). Given that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are well-characterized, potent inhibitors of COX1 and 2, it is plausible that prescription of NSAIDs after biologic scaffold implantation could alter the endogenous constructive tissue remodeling process.
The central theme of this project is that COX2 up regulation is a critical component of the biologic scaffold initiated tissue remodeling program and administration of NSAIDs may alter the overall tissue remodeling outcome. Aim 1 seeks to establish a firm mechanistic link between biologic scaffold stimulated COX2 up regulation in macrophages and its effect on myogenesis using a well-established in vitro system. This system will then be utilized to determine the effect(s) of NSAIDs on both the macrophage phenotype and the myogenic response. Aim 2 furthers these studies by investigating macrophage phenotype, myogenesis, and COX2 expression in a well-established muscle injury model. This model will then be utilized with NSAID treatments to determine the effect of NSAIDs on the remodeling outcome. The completion of these studies will greatly enhance our understanding of the molecular events that biologic scaffolds trigger to initiate a constructive tissue remodeling response, and if NSAIDs alter those events and the remodeling outcome. Together these studies may provide a new metric for the design of next generation biologic scaffolds as well as provide useful information to physicians utilizing regenerative medicine technologies who may be prescribing NSAIDs for post-operative care.
This project will enable the student to:
- Assist in design, development, execution, and implementation of basic / translational research projects.
- Gain experience with cell culture, including primary cell co-culture systems.
- Gain exposure to various aspects of pre-clinical research, including small animal surgery, necropsy, tissue processing & analysis.
- Exposure to areas of regenerative medicine, tissue engineering, cellular / molecular immunology, cell biology, or related fields (coursework acceptable)
- Experience in biomedical wet lab research (previous lab experience preferable)