Hospital-based, lead investigator Ron Tompkins and his team developed a research network to tackle the most important biological problem that hinders major medical advances in fighting the serious systemic innate immune response and sometimes fatal consequences of the body’s response to serious trauma or burn injuries. Serious complications like sepsis and multisystem organ failure remain the most common late complications of severe trauma and burns. Drug treatments to date for trauma, burns, and sepsis have not obtained the anticipated success for a number of reasons, in part due to the heterogeneity of the treated population, the inability to recognize the early clinical signs, and an incomplete understanding of the underlying pathophysiology of the septic response. Identification of multiple surrogate markers that reflect the nature and severity of the inflammatory response, the status of the coagulation and fibrinolysis systems, and the magnitude of organ injury would be effective in identifying injured patients at risk of an adverse outcome, and those who may benefit from therapeutic interventions.
Read MoreBy gathering well-recognized doctors, scientists, and investigators with a very broad and comprehensive base of expertise and “gluing” them together to tackle this tough problem, Tompkins’ team of disparate researchers many of whom had not been previously involved in trauma research established standards and broadened the scientific infrastructure in the field of injury research where little had existed previously. With scientific, financial, and administrative oversight of 22 subcontracts and nearly 100 surgeons, scientists, and nurses for a total cost of over $100 million, the “Inflammation and the Host Response to Injury” Glue Grant (U54-GM062119) awarded to the Massachusetts General Hospital became the 10th largest award given by the NIH during its 10 years’ funding and the largest, single award MGH had every received from the National Institutes of Health. The five-year program began on October 1, 2001 and was awarded a second five years of funding starting on September 30, 2006. It was U54-funded with two no-cost extensions through August 31, 2013.
The particular challenges for the program:
- Create evidence-based guidelines for the consistent clinical treatment of severely injured trauma and burn patients
- Collect, sort, and count human white blood cells for genomic and proteomic testing
- Analyze, archive, and retrieve high throughput, genome-wide expression and proteomic data
- Integrate genome-wide expression data with clinical outcomes
- Develop new statistical, bioinformatics, and computational tools to extract biological information from the massive, complex data sets
The Program amassed data from over 2,600 blunt-injured and burn patients enrolled in the clinical studies from 2003-2010, at several leading U.S. academic Level I trauma and burn centers using monitored standard operating procedures (SOPs, clinical care guidelines) developed at study onset. An extensive database on patient characteristics, injury severity, clinical treatment, outcomes, complications like sepsis and organ failure, and SOP compliance was created.
In addition to the patient studies, the program carried out many studies in mouse models designed to mimic the inflammatory conditions of human trauma and burns, and a condition called endotoxemia that has the same characteristics as sepsis. Much progress had been made to make the mouse models highly consistent with the human conditions, but the Program quickly recognized that there are limits to this mimicry. In the mouse studies, Glue Grant investigators confirmed the gene expression data with a quantitative laboratory technique and showed excellent agreement. Because the costs were very high to reproduce the microarray data for thousands of genes by this technique, the Program omitted the mouse studies in the second half of the program.
The Inflammation Glue Grant program deliverables and contributions include:
- A well-annotated clinical database of rich genomic and proteomic information from patients and healthy individuals
- New technology for application in clinical studies (microfluidic cell separations, novel custom gene chips)
- Novel analysis tools to explore the genomic and proteomic data
- Sets of genes with high predictability of patient recovery paths
The Glue Grant leadership team believes that the preservation of its mouse and human data sets and the ongoing analysis of the data are important activities to continue post-Glue Grant funding. The bioinformatics resources generated within the Glue Grant program – the information system and data visualization tools – are an important legacy of the Glue Grant Program and are partially supported by a National Institute of General Medical Sciences follow-on, legacy award entitled “Bridging Sustainable Distribution of TRDB Bioinformatics Resources” (R24-GM102656) that provides a “bridge” toward sustainability of the bioinformatics products as community-wide scientific resources.
The clinical trials infrastructure developed in the Glue Grant program has been sustained to the extent possible with smaller NIH awards as the investigator group works to organize a clinical trial for trauma patients, utilizing the knowledge and tools developed in the program.
Contact
| Ronald Tompkins, MD, ScD | Wenzhong Xiao, PhD | Grace McDonald-Smith, MEd |
| 617-726-3447 | 617-724-7261 | 617-726-1853 |
Visit the Glue Grant program website