NHLBI, part of the National Institutes of Health, offers Program Project grants to researchers who seek to conduct several, interrelated research projects that focus on one question. In this case, the question is: can intracellular signaling pathways be manipulated to reduce inflammation in blood vessels?
In the past, experts believed that atherosclerosis, or hardening of the arteries, developed when too much cholesterol clogged arteries with fatty deposits called plaques. When blood vessels became completely blocked, heart attacks occurred. Now most believe that the reaction of the body's immune system to fatty build-up, more than the build-up itself, creates heart attack risk. Vessel walls mistake fatty deposits for intruders, akin to bacteria, and call for help from the immune system. White blood cells arrive to prevent infection, but also cause inflammation that makes plaques more likely to swell, rupture and cut off blood flow.
"At the time of their first heart attack, half of today's patients have normal cholesterol levels," said Bradford C. Berk, M.D., Ph.D., Co-Director of the Cardiovascular Research Institute at the medical center, and the grant's principal investigator. "We clearly need to do more than reduce cholesterol levels to prevent heart attacks, and gaining control of inflammatory pathways would enable us to take treatment beyond its current limits."
For the first project, Berk's team will study mechanisms by which oxidative stress promotes inflammation, and by which steady blood flow inhibits inflammation. A key protein that protects against atherosclerosis is thioredoxin, the activity of which is increased by steady flow, but inhibited by thioredoxin-interacting protein (TXNIP). Berk's project will investigate how steady flow inhibits TXNIP, enabling thioredoxin to better protect blood vessels.
Researchers believe that decreasing TXNIP will decrease the ability of white blood cells to "stick" to blood vessel walls, an early step in the formation of plaque. Thus, interfering with TXNIP represents an important thrust in drug development. Medical center researchers recently revealed inhibition of TXNIP to be a key mechanism by which steady blood flow, brought on by exercise for example, protects vessels from atherosclerosis. TXNIP provides the link because it is both sensitive to blood flow and involved in the regulation of inflammation.
Project two, under the direction of Jun-ichi Abe, M.D., Ph.D., will study the role in inflammation of peroxisome proliferator-activated receptor gamma (PPAR gamma). PPARs decrease the production of cytokines, secreted mediators that drive inflammation in blood vessel walls. Thus, PPAR gamma is already the target of a number of medications, including the thiazolidinediones used in diabetes. Researchers plan to explore whether extracellular signal-regulated kinase 5 (ERK5), an enzyme that drives PPAR gamma to shut down cytokines, can reduce inflammation through a mechanism different than that used by current medications.
In project three, Mark B. Taubman, M.D., Co-Director of the CVRI, will explore a new method to inhibit production of the inflammatory cytokine termed monocyte chemoattractant protein-1 (MCP-1). In an early step in atherosclerosis, MCP-1 moves white blood cells to the arterial wall where they absorb cholesterol and drive inflammation. MCP-1, like all proteins, is built based on blueprints encoded in its specific messenger RNA. Taubman will investigate methods to reduce the stability of MCP-1 mRNA and thereby decrease the amount of MCP-1 protein created. This approach differs from those that interfere with MCP-1 at other steps in the genetic process (e.g. at transcription), but that also tend to disrupt genes critical to normal cellular function. Medical center researchers hope to tailor the structure of MCP-1 mRNA to make it less stable, or more likely to be broken up by competing chemical reactions before it can be translated into MCP-1 protein. To do so, researchers will examine whether the glucocorticoid dexamethasone can make MCP-1 mRNA less stable, and whether they can interfere with platelet-derived growth factor, which promotes its stability.
The final project, led by Chen Yan, Ph.D., will examine whether cyclic nucleotide phosphodiesterases (PDEs) can protect against inflammation and oxidative damage caused by nitric oxide. Immune system cells called macrophages destroy bacteria by releasing nitric oxide (NO), a highly reactive free radical that tears apart the DNA of intruding bacteria. In the case of atherosclerosis, macrophages mistake fatty deposits as bacteria and release too much NO, causing oxidative stress that damages otherwise healthy tissue. Dr. Yan's group will study the ability of specific PDE-1 inhibitors to decrease atherosclerosis in animal models. The fact that a PDE-5 inhibitor (Viagra) is already a successful treatment for another condition lends credibility to this treatment approach.
"This type of grant recognizes the power of collaboration in research, as opposed to individual researchers all going in their own directions," Taubman said. "Our team has a history of working together, with 25 publications jointly authored by two or more members of the team in the last four years. Many of the papers were the first to describe molecules or processes involved in inflammation, and we expect the grant to make possible many more firsts."