Research underway in the Anesthesia Center for Critical Care Research (ACCCR) at Massachusetts General Hospital focuses on elucidation of the fundamental mechanisms underlying central problems of intensive care medicine including sepsis, acute respiratory failure, blood transfusion, pulmonary hypertension and cardiac dysfunction. Our goal is to develop novel strategies designed to improve outcomes in critically ill patients.
The center takes a multidisciplinary approach to research. Clinicians and basic scientists collaborate on various research studies on small and large animal models.
Current projects include:
Warren M. Zapol, MD, director
Research in the Zapol Lab is directed at understanding a wide range of critical illnesses that can be therapeutically treated with novel inhaled gases. Inhaled nitric oxide (NO) is a central focus of the laboratory research, both as a selective pulmonary vasodilator and a safe method for loading the body with NO donor molecules. As a selective pulmonary vasodilator, inhaled NO is used to treat pulmonary hypertension and to improve ventilation-perfusion matching of the lung. NO inhalation leads to the formation of circulating NO metabolites, which after conversion to NO, can neutralize oxygen free radicals, activate soluble guanylate cyclase (to make cGMP) and prevent the side effects of excessive scavenging of endogenous NO molecules by transfusion of stored red cells. The prevention and treatment of acute lung injury is also studied with murine models of ventilator-induced lung injury and transfusion.
Our research group also studies inhaled NO therapy in children with cerebral malaria and in adults with stored blood transfusion. Animal models used in the laboratory extend from mice to sheep, with a special focus on translational research to improve the care of critically ill patients.
Ken Bloch Lab Our laboratory has long-standing interests in the mechanisms regulating pulmonary vascular and ventricular remodeling, as well as the role of bone morphogenetic protein (BMP) signaling in cardiovascular homeostasis. During the course of these studies, we have developed and characterized murine models of a broad spectrum of cardiopulmonary disorders including myocardial infarction, congestive heart failure, pulmonary hypertension and acute lung injury.
We have explored how mutations in the gene-encoding bone BMP receptor type 2 (BMPR2) cause primary pulmonary hypertension. In an exciting collaboration with Randall Peterson, PhD, and Paul B. Yu, MD, PhD, we have identified the first known small molecule inhibitors of BMP signaling. Using these inhibitors, we have elucidated critical roles for BMP signaling in a variety of important diseases including heterotopic ossification, anemia of inflammation, atherosclerosis and vascular calcification.
We also collaborate with Thomas Wang, MD, and Christopher Newton-Cheh, MD, MPH, in studies of the mechanisms by which genetic variants in the NPPA/NPPB gene locus modulate natriuretic peptide levels and contribute to the regulation of blood pressure. One of these genetic variants, re5068, lies in the NPPA 3’ untranslated region (3’UTR). Our laboratory identified and functionally characterized a microRNA, miR-425, that targets the NPPA 3’ UTR when it is encoded by the rs5068 major allele but not when it is encoded by the minor allele. Ongoing studies are directed towards understanding how microRNAs regulate natriuretic peptide biosynthesis and the pathophysiologic effects of modulating microRNA signaling.
Donald Bloch Lab
The long-term objective of the Donald Bloch Lab is to identify the putative infectious agent or agents that initiate autoimmune disease. This goal is especially difficult to attain because the first events that trigger an autoimmune disease may occur years, if not decades, before the occurrence of clinical symptoms. Recent studies show that autoantibodies may be detected many years prior to clinical manifestations of disease. Autoantibodies and the antigens that they recognize may provide the only clues to the events that occurred early in the course of the disease.
A second objective of our research is to identify and characterize novel subcellular, macromolecular structures. Previous investigators have shown that the antigens recognized by human autoantibodies have critical roles in cellular biology. Dr. Bloch has taken advantage of autoantibodies and recent advances in proteomics to characterize novel structures in the cell nucleus and cytoplasm.
A third objective of our research is to develop a novel inhibitor of B cell differentiation. This project is an outgrowth of earlier studies, which resulted in identification of Sp110, a leukocyte-specific autoantigen that localizes to cellular structures known as nuclear bodies. Dr. Bloch and colleagues identified mutations in the gene encoding Sp110 as the cause of an autosomal recessive disorder known as veno-occlusive disease with immunodeficiency (VODI). Patients with VODI have a defect in the class switch recombination step of B cell development and therefore fail to make antibodies of the IgG and IgA isotypes. Dr. Bloch is developing small molecule inhibitors of Sp110 function as an approach to inducing immunosuppression in patients with autoimmune diseases.
The Buys Lab focuses on three research topics. In the first project, we are seeking to gain insight into the role of NO-cGMP signaling in the regulation of blood pressure. We are evaluating the role of renin and 20-HETE signaling in the development of hypertension in mice deficient in the NO-activated cGMP-producing enzyme soluble guanylate cyclase (sGC). We are collaborating with Dr. Kenneth Bloch and Dr. Newton-Cheh, to characterize the function of GUCY1 gene variants associated with the regulation of blood pressure.
In the second project, we are studying the role of NO-cGMP signaling in the development of open angle glaucoma. This project includes characterization of a new mouse model of glaucoma leading to the identification of novel biomarkers and therapeutic targets in clinically-relevant samples. In other collaborative projects, we are characterizing the role of NO-sGC signaling in stroke, myocardial infarction, cardiac arrest, cardiac dysfunction associated with systemic inflammation, gastrointestinal motility, erectile function, renal function, and brain and lung development.
Finally, we are collaborating with Dr. Zapol and Dr. Daniel Costa on a project to test the hypothesis that altered NO-cGMP signaling underlies the capability of Antarctic Weddell seals to withstand severe bouts of hypoxia as they dive for prolonged periods of time.
Our research has focused on the molecular mechanisms responsible for the cardio-cerebral dysfunction and injury often found in patients suffering critical illness including sepsis, cardiac arrest and CPR, and neurodegenerative disorders. Goals of our current research programs include elucidation of the molecular mechanisms responsible for the biological effects of nitrous oxide (NO) and hydrogen sulfide (H2S) and to develop novel therapeutic strategies.
In collaboration with Dr. Kenneth Bloch, we found that breathing low levels of NO starting hours after resuscitation from cardiac arrest and CPR markedly improves neurological outcome and survival in mice. Given the safety track record of inhaled NO, these results may be rapidly translatable into clinical practice. We are currently developing a phase I/II clinical trial to examine the feasibility of treating patients recovering from out-of-hospital cardiac arrest with inhaled NO.
We recently developed a novel sulfide-releasing NMDA receptor antagonist that exhibits enhanced neuroprotective effects with low toxicity against neurodegenerative disorders. We are currently in the process of optimizing the candidate molecules for further development and testing their effects in mice models of neurological disorders including ischemic spinal cord injury, Parkinson’s disease, and those resulting from cardiac arrest and CPR.
In very recent studies, we discovered a previously unrecognized role of the protein S-nitrosylation in beta-adrenergic receptor-dependent signaling in cardiomyocytes. Ongoing studies are directed towards elucidating the molecular mechanisms responsible for the effects of S-nitrosylation using mutageneis and gene transfer in cultured cardiomyocytes and a variety of genetically modified mice models.
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Disabled Access: yes
Members of the ACCCR are based on the main campus at Mass General and in the Charlestown Navy Yard Building 149.