The Lungs

Selected recent major discoveries:

• Discovery of a completely new mechanism of gene regulation: Cytokines (the body’s instant messaging system) must be very tightly regulated in order to enable host defense against pathogens without destroying the body tissues via bystander injury.  Transcripts for cytokines and other dangerous messages are repressed by endogenous small RNA molecules known as miRNAs, but whether and how miRNAs might be altered during infection and immunity are poorly understood.  Deep sequencing had previously revealed that miRNAs sometimes contained nucleotides such as uridines on their ends which were not encoded by the genome, but how these nucleotides got there and what they meant were unclear.  Dr. Mizgerd identified for the first time an enzyme responsible for placing uridines on the ends of miRNAs and demonstrating that uridylation of miRNAs by this enzyme relieved them of their ability to target transcripts.  In addition to the cytokines essential to preventing lung infection, this completely new mechanism of gene regulation is likely relevant to many transiently expressed proteins. (Nature Cell Biol 11:1157, 2009)

• Discovery of molecular basis for defective lung development: It was previously well-recognized that genetic, environmental, or nutritional defects in vitamin A signaling can have profound repercussions on the development of the respiratory system.  Dr. Cardoso demonstrated that retinoic acid (the biologically active form of vitamin A) functions during lung development by simultaneously enhancing signaling through one pathway (Wnt) and limiting signaling through another (TGF-b).  Restoring these pathways rescued lung bud formation in mice with retinoic acid deficiency.  This discovery illuminates a previously unrecognized signaling pathway as the molecular basis underlying congenital disease resulting from genetic, environmental, or nutritional defects in vitamin A signaling which has large implications on global health. (J Clin Invest 120:2040, 2010).

• New research program funded to elucidate genetic disease and empower stem cell therapy: Pulmonary Center investigator Dr. Kotton received an NHLBI Grand Opportunity (GO) Grant providing over a million dollars per year entitled “Characterization of Human Hematopoietic and Endodermal Progenitors Derived from iPS Cells Free of Reprogramming Transgenes.”  The studies will use a novel excisable reprogramming vector to generate “clinical grade” iPS cells (free of transgenic sequences) from patients with cystic fibrosis or with alpha-1 antitrypsin (AAT) deficiency, and to test whether the differentiation of these patient-derived cells differs from normal human iPS cell differentiation. By recreating the disease in cell culture, these studies open exciting new avenues for studying underlying biology and potential therapeutic strategies for these 2 most common inherited forms of lung disease.