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Tuesday, August 4, 2009
Bernard Kinane, MD
The regulation of chemokine inflammatory cell migrationChronic pulmonary inflammation of the infected CF airways has been shown to be mediated by chemoattractant cytokines, called chemokines. Chemokines are released locally in response to infection and activate pertussis toxin sensitive G protein coupled receptors on the surface of leukocytes. We, working with Drs Marc Tessier-Lavigne and Kathryn Moore, have recently defined a novel inhibitor of these pathways. We found that the neuroregulatory molecule, Netrin-1, inhibits inflammatory cell migration. It is expressed on vascular surface where it regulates the migration of intravascular leukocytes (figure 1). Thus we have identified a finely tuned pathway to regulate cell migration. This is potentially a novel target for drug design (1).
Regulation of lung development in congenital diaphragmatic herniaCongenital diaphragmatic hernia (CDH) is a lethal birth defect in which the diaphragm fails to form completely in the developing fetus and affects one in 3,000 live births. The defect is invariably associated with immaturity of the lungs. The mortality from the malformation remains as high as 60%, and the number of deaths per year are 25% of the number from congenital heart disease during the first year of life, or 1.3 times the number of deaths due to leukemia from age 0 to 14 years. With Dr Jay Schnitzer, we have explored the role of mitogen-activated protein (MAP) kinase in CDH-associated hypoplastic lungs in vitro and in vivo. We have demonstrated significant differences in the levels of MAP kinase phosphorylation between CDH and normal fetal lungs, and have shown increased phosphorylation, towards that observed normally, in CDH lungs after treatment with vitamin E in vivo (2). We, working with Drs Jay Schnitzer and Patricia Donahoe have extended this work to define potential mutation in these pathways in affected patients.
Identification of critical factors in the regenerating tissuesAmphibians and flatworms are capable of regenerating lost body appendages. However, the key initiation factors need to be defined by functional studies. We are exploring why flatworms regenerate and mammals do not.
Using an extract derived from flatworm regenerating tissues, we are defining critical regulatory proteins and RNAs. We have found a number of key regulatory RNA. We focused on small RNA (miRNA) which have been shown to be critical switches in many cellular processes. They are necessary for coordinating very basic physiological processes. Despite physical problems with flatworms, we have been able to isolate these miRNA switches from planaria and found them to be identical to those identified in other species including worms and flies. Specifically we found that three novel miRNAs called 14286, 13450 and 11208 that are down regulated. These are very attractive candidates because miRNA turn off genes, so one could envisage a situation where these miRNA are regulation important genes that control regeneration (figure 2).
Also early work suggests that macrophages have a critical role in regeneration via clearance of apoptotic cells. Understanding how these cells clear wound debris without activating inflammation is critical. we have also begun to make significant progress. We have now found that macrophages in planaria are functional. We found that they clear apoptotic cells (dead cells) as well as parasites. But what was surprising was the location of the apoptotic cells. We expected that the cells would die early in the wounding and regeneration process. This is not the case. We found that the stem cells start proliferating and form an amorphous group of cells called the blastema. Once this blastema undergoes maturation, a large population of cell undergo apoptosis (see figure 3).
They are cleared in an organized manner. In mammals such a clearance would induce inflammation and scarring. Macrophages are the central cell for the clearance of dead cells and infections. Recently it is been recognized even in mammals that these macrophages can go in two directions to clear dead cells and bacteria: an inflammatory pathway and non inflammatory pathway. We have a lot insight into the inflammatory pathway but less is know about the non inflammatory pathway. Our colleagues, Dr Adam Lacy, has found that this non inflammatory pathway may be central to inflammatory bowel disease. Thus understanding how planaria clean up the wound during regeneration may have important implications for other important diseases that affect millions of people.
Carbon dioxide is critical in the process that drives respiration. The muscarinic cholinergic nervous system plays an important role in this process. Defects in this system have been noted in Congenital Central Hypoventilation (CCHS). The RET proto-oncogene plays a key role in neural crest development from which this parasympathetic nervous system evolves. We showed that the majority of RET knockout mice have lost the normal hyperventilatory response to inhaled CO2. Thus the RET gene is important for the development of the neural elements that control ventilation. We have broadened the scope of these studies to identify defects in patients with CCHS and normal babies in the early postnatal period.
Our recent work has explored the regulation of respiratory control in the newborn period. Dr Christina Scirica and I working with Lili Cerar-Kornhauser found that significant oxygen desaturations occur in healthy term newborns while placed infant car safety beds or infant car safety seats. The cause of these apneas is a combination of airway obstruction and chest wall compression (3, 4).
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