Dearth - 2019

Regenerative Biosciences Division Extremity Trauma & Amputation Center of Excellence
Lab Chief
Christopher L. Dearth, Ph.D.
Walter Reed
Mentor Name
Christopher L. Dearth, Ph.D.
Stephen M. Goldman, Ph.D.
Mentor Telephone
(301) 319-2461
Laboratory And Project Description

Laboratory

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 Servicemembers 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 Servicemembers. 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

Project Description

In the event of a traumatic orthopaedic injury affecting a synovial joint, damage to the articular surface often occurs either through direct insult or indirectly as a result of subsequent incongruities and altered loading.  These sites subsequently result in a high reoccurrence of injury and progressive degeneration through a process coined Post Traumatic Osteoarthritis (PTOA).  PTOA is pervasive and represents a significant socioeconomic burden as it is estimated to result in expenditures on the order of 15 billion dollars per year within the United States civilian sector, and represents the most prominent deleterious secondary health condition leading to medical discharge following combat related trauma in our military.  As such, new interventional strategies which minimize or prevent progressive degeneration of the joint are of great interest to facilitate greater joint function and quality of life for the patient.  As of now, no such disease modifying, FDA-approved treatments exist.

The role of inflammatory and anti-inflammatory cytokines in driving the progression of PTOA with respect to catabolic and anabolic processes within the cartilage is becoming of increased interest for approaches aimed at disease modification.  In particular, inhibition of key cytokines such as IL-1 and TNF-α has been identified as a potentially potent target for slowing the progression of PTOA.  Simply modulating the local inflammatory response, however, is unlikely to lead to effective regeneration of defects to the articular surface, as such processes require the highly coordinated interplay between resident chondrocytes and local chondroprogenitor cells (i.e. marrow and synovial derived MSCs).  Multiple regenerative approaches for cartilage have been identified, validated in preclinical models and are currently being evaluated in clinical studies.  For example, an analog of kartogenin, a recently identified small molecule mediator of chondrogenesis, cartilage and bone repair which is active in preclinical models of OA, will be evaluated in a Phase I clinical study in OA patients.  Limitation of inflammation and promotion of joint tissue regeneration may be a powerful approach to this complex disease.  As such, we will test the hypothesis that concurrent administration of infliximab, an FDA approved TNF inhibitor, and kartogenin will promote anti-inflammatory and pro-regenerative microenvironments within the synovial cavity, respectively, such that the anti-inflammatory actions of infliximab will enhance the regenerative efficacy of kartogenin resulting in greater preservation of articular surface thickness with a concomitant improvement in function.  Primary outcome measures will include end-stage regenerative assessments of the articular surface via quantitative micro-CT imaging and a gait analysis.  Secondary outcome measures will include quantitative histological and molecular analysis of matrix deposition and cellular infiltration of the articular surface in addition to histomorphometric analyses of the cartilage to determine the severity of the OA.  

This project will enable the student to:

  1. Assist in design, development, execution, and implementation of basic / translational research projects.
  2. Gain exposure to various aspects of pre-clinical research, including small animal surgery, necropsy, tissue processing & analysis.
  3. Gain experience with translational imaging modalities (i.e. micro-CT) and associated image processing and data reduction.

Required Skills:

  1. Exposure to areas of regenerative medicine, tissue engineering, cellular / molecular immunology, cell biology, or related fields (coursework acceptable)
  2. Experience in biomedical wet lab research  (previous lab experience preferable)
  3. Experience in technical computing (coursework acceptable)