Research Areas

The overall goal of the Noble Laboratory is to understand the molecular mechanisms of lung injury, repair and fibrosis. Pulmonary fibrosis occurs in a variety of clinical settings and constitutes a major cause of morbidity and mortality; developing effective therapies represents an enormous unmet medical need. Idiopathic pulmonary fibrosis (IPF) is the most common and most severe form of idiopathic interstitial pneumonia. It is often relentlessly progressive, leading to death from respiratory failure within two to five years of diagnosis in the majority of instances. No effective medical therapies exist. Lung transplant is the only therapy to prolong life.

Evidence has emerged implicating a combination of environmental, aging and genetic factors that together may create conditions in the alveolar epithelium making it susceptible to injury from either unknown endogenous factors or exogenous insults such as viral infection or microaspiration. We tackle this noxious problem by investigating the following areas:


Innate Immunity and Matrix in Lung Injury and Repair

The lung is constantly in perpetual contact with our environment, and it must have evolved mechanisms for repairing injury caused by exogenous noxious agents. The timely repair of lung injury is essential and determines outcomes of life or death. Inadequate repair can result in abrupt respiratory decompensation or more protracted handicap with subsequent fibrosis that is ultimately fatal. The alveolar epithelium is the critical impediment to noxious injury and represents both our most vulnerable point of attack and our greatest resource for overcoming assault. The mechanisms that constitutively protect the distal alveolar space and promote progenitor cell renewal of wounded alveolar epithelial type 2 cells (AEC2) are unknown. One of our areas of research is to study the role of interactions between the cell surface glycosaminoglycan hyaluronan and innate immune components in protecting lungs from injury and in stem cell renewal.

TLR2 and TLR4 act as key sensors of the extracellular matrix component hyaluronan in the lung. From O'Neill LA. Nat Med. 2005 Nov;11(11):1161-2.

 

Molecular Mechanisms of Lung Fibrogenesis

We are studying the sources of fibrotic fibroblasts, fibroblast invasiveness and transcriptional control of fibroblast activation.

Model of the relationship between ER stress and lung fibrosis. From Noble PW, et al. J Clin Invest. 2012 Aug 1;122(8):2756-62.

  

Proposed mechanisms of severe lung fibrosis. From Noble PW, et al. J Clin Invest. 2012 Aug 1;122(8):2756-62.

 

Role of Chemokines and Chemokine Receptors in Lung Injury and Repair

We are studying the immunoregulatory and molecular roles of CXCL10, CXCR3, CXCL12 and CCL2 in lung injury and repair. We are using transgenic and knockout mice to define the mechanisms of these chemokines and their receptors in pulmonary fibrosis, especially stem cell recruitment and maintenance, inflammatory cell recruitment and activation and epithelial cell integrity.