The Future of Anesthesiology Education, Part 3

This article represents the final installment of FAER’s award recipients. Previous winners, Raymond A. Zollo, M.D., and Mark A. Gerhardt, M.D., Ph.D., were featured in the July 2003 ASA NEWSLETTER. Li-Ming Zhang, M.D., and Srinivasan G. Varadarajan, M.B. were featured in the August 2003 ASA NEWSLETTER.


Research Training Grants ($175,000 for two years)

Ozan Akca, M.D., University of Louisville, Louisville, Kentucky: “The Role of Hypercapnia in Preconditioning of the Brain.” Mentor: Avitar Schurr, Ph.D.

Exposure to hypercapnia may provide protection against subsequent ischemia in brain tissue. The goal of our project is to determine if this protection can be demonstrated in rat brain slices and explore possible mechanisms. Hippocampal slices will be exposed to hypercapnia or normocapnia and then to hypoxia. The percentage of neuronally functional slices will be determined after reoxygenation. Pharmacological blockers of KATP channels or nitric oxide synthase will be used to give indirect evidence of K channel and nitric oxide’s mechanistic involvement. We hypothesize that 1) short-term application of mild and moderate hypercapnia preconditions hippocampal slices, 2) this preconditioning is mediated by nitric oxide and KATP channels, 3) metabolic acidosis also preconditions the slices to ischemic injury and 4) hypocapnia preconditioning worsens the outcome of ischemic injury. Inhalation anesthetics also protect against ischemia. We will therefore test the ability of hypercapnia and sevoflurane to synergistically precondition hippocampal brain slices. Finally we will test the hypothesis that in vivo hypercapnia induces preconditioning against cardiac arrest-induced cerebral ischemic damage. This research will be the first step in determining the important question of whether exposure to hypercapnia protects patients against future ischemic injury.

Eduardo N. Chini, M.D., Mayo Clinic Foundation, Rochester, Minnesota: “Role of the Accessory Protein FKB12 in the Development of a Malignant Hyperthermia Phenotype.” Mentors: Gary C. Sieck, Ph.D., and Denise J. Wedel, M.D.

Malignant hyperthermia (MH) is a disease that is closely related to central core disease, which is characterized by muscle rigidity and abrupt increases in body temperature during general anesthesia. Furthermore, some evidence indicates that patients with muscular dystropy and other muscle diseases are at increased risk for developing an MH crisis. The so-called ryanodine calcium channel (RyR) is clearly involved in the pathogenesis of this disease. The present proposal is to determine the role of the accessory skeletal muscle protein FKBP 12 on the development of MH. This protein is known to be associated with the RyR and regulates its function. The results of this project may lead to a better understanding of the pathogenesis of MH and to the development of new strategies for the treatment and diagnosis of MH and would benefit patients with muscular diseases, including muscular dystropy and central core disease.

Research Starter Grants ($85,000 for two years)

David P. Martin, M.D., Ph.D., Mayo Clinic and Foundation, Rochester, Minnesota: “Adrenergic Sweating in Painful Neuropathies.” Mentor: Phillip A. Low, M.D.

Neuropathic pain poses a great challenge to patients and to the physicians who treat them. A lack of objective clinical diagnostic tests limits our ability to study and treat these conditions. While pain is inherently a subjective experience, sympathetic functions such as sweating and vasomotor tone can be measured objectively. Pain and sympathetic signals travel along similar small, nonmyelinated fibers in the periphery. We believe that patients with neuropathic pain may have parallel abnormalities in their sympathetic nerves. Specifically we are investigating a phenotypic reversion of sweat gland innervation from normal cholinergic to abnormal adrenergic neurotransmission. This may explain the abnormal sweating seen in painful neuropathies and may be related to the mechanism underlying neuropathic pain. We hope that our studies will increase the understanding of neuropathic pain and may provide objective clinical tests that will assist in the care of patients with these painful conditions.

Eugene W. Moretti, M.D., Duke University, Winston-Salem, North Carolina: “Genetic Polymorphisms and Their Relationship to Sepsis in the Surgical Patient.” Mentor: Debra A. Schwinn, M.D.

Sepsis syndrome results from an infectious cause that is associated with severe systemic inflammatory response and organ failure. There are 751,000 cases of sepsis annually in the United States, with an annual cost of $16.7 billion. Approximately 35 percent to 45 percent of patients who experience sepsis will die. Our research is designed to identify those surgical patients at increased risk by identifying specific gene sequences that are associated with sepsis. This current study may enable us to more effectively risk-stratify our critically ill populations. These gene sequences could ultimately be used to define inclusion criteria for further clinical trials in sepsis. Genetic stratification may allow us to avoid treatment failure because of a poorly defined patient population; hence, experimental drugs may stand a better chance of providing clinical benefits by improving survival. Knowledge in this area may contribute to modulating the activity of the physiologic pro- and anti-inflammatory mediator systems.

 

Research Fellowship Grant ($50,000 for one year)

Omid C. Farokhzad, M.D., Brigham and Women’s Hospital, Boston, Massachusetts: “Nucleic Acid Ligands as Escort Molecules in Targeted Therapy.” Mentor: Robert S. Langer, Ph.D.

Controlled-release polymer systems that can encapsulate drugs and release them in a regulated fashion are used in virtually all areas of medicine, including anesthesiology. The purpose of our investigation is to develop a technology to target the delivery of controlled-release polymers in a disease-specific manner. As proof of the concept, we intend to develop delivery vehicles to target prostate cancer cells using nucleic acid ligands (also known as aptamers). We will use a large, random oligonucleotide library (1015 oligos) and the Systemic Evolution of Ligands by Exponential Enrichment (SELEX), together with a novel selection/ counter-selection screening approach using normal prostate and prostate cancer tissue-microarrays, to isolate aptamers that bind to prostate tumor-antigens specifically. Next, we will conjugate the aptamers to drug-encapsulated controlled-released nanoparticles (~200 nm) to generate nanoparticle-aptamer bioconjugates for prostate cancer therapy. Our novel screening strategy for isolating disease-specific aptamers, together with the technology to use aptamers for targeting control-release polymer systems, may be used to generate bioconjugates for treatment of other important human diseases.