Initial Research Focus for the Precision Medicine Program

National Jewish Health sees patients with respiratory and related conditions from all over the world. Current research within the Precision Medicine program focuses on COPD, which is the 3rd leading cause of death in the US. The organization has secured grant funding for a study that utilizes data from a large cohort of current and former smokers from the COPDGene study.

Study Overview: “Personalized molecular approach to diagnosis and treatment of COPD and Emphysema”

Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the US (1, 2). Although COPD occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develops chronic airflow limitation and/or destruction of distal airspaces (emphysema). The goal of this proposal is to identify molecular and genomic signatures in COPD and emphysema patients that can be used to target individualized therapies. Recent technical advances in genetics, genomics, proteomics, and metabolomics (Omics) provide a new opportunity to conduct large scale investigations into the molecular basis of complex human diseases such as COPD and emphysema; however, roadblocks to this approach include the lack of large cohorts of well phenotyped COPD patients with biologic samples. To overcome these deficiencies, we have created a 2000 subject cohort of current and former smokers with and without COPD and emphysema within the NIH sponsored COPDGene® cohort.

In recently published pilot studies, we have shown that we can use genomic and metabolomics approaches to identify novel molecular pathways that appear to be deranged in certain patients with COPD and emphysema. Examples of these pathways include ceramide/sphingolipid and Arghef1 signaling. Furthermore, in animal and cell culture experiments we have found molecular therapies that specifically target these pathways (e.g. sphingosine 1-phosphate analogues and thromboxane antagonists respectively) and can reverse some of the COPD and emphysema-like changes in mice exposed to cigarette smoke. Although these preliminary Omics studies may result in promising new diagnostic tests and therapies for COPD patients, the challenging funding environment at the NIH has left few resources to follow up on the promising work in genomic signatures of COPD and emphysema.

We hypothesize that these genomic approaches, when used in a larger, more diverse population of COPD and emphysema patients, will identify additional novel pathways that can be targeted for drug development. To efficiently accomplish these goals, we propose to capitalize on existing stored lung and blood samples in the well-characterized COPDGene cohort. These genomic data sets can be further leveraged by integrating with existing genetic and metabolomics datasets generated prior via NIH awards. To accomplish this, we propose two specific aims.

SA1: Generate genomic profiles of COPD and emphysema using existing stored blood and lung samples from COPDGene cohort.

  1. Identify key molecular features and pathways associated with COPD and emphysema.

  2. Identify critical sub-networks and pathways associated with clinical phenotypes of COPD and emphysema disease using integrated omics datasets.

  3. Develop predictive models of critical pathways and factors involved in disease onset, severity and susceptibility to identify therapeutic targets for intervention to control the development of lung disease.

SA2: Determine the mechanism(s) linking dysregulation of candidate pathways to the development of cigarette smoke (CS)-induced lung inflammation and emphysema in animals and cell models of COPD.

  1. Use gene-targeted mice to study specific candidates in animal and cell models of CS-induced injury.

  2. Determine if molecular inhibition of specific metabolic targets will inhibit key pathogenetic mechanisms of cigarette smoke induced lung disease such as emphysema, resolution inflammation, and impaired immunity in airway infections.

Rationale/Impact: This research addresses a fundamental gap in our understanding of COPD and emphysema pathogenesis (i.e. genomic profiles of COPD). It is cost effective because it uses existing genetic and metabolomic data from a large cohort of superbly phenotyped COPD and control subjects (current and formers smokers). Ultimately, our work will lead to the development of a novel mechanistic-based classification scheme for COPD phenotypes and to the discovery of novel and previously unsuspected molecular targets with profound clinical implications in future patients with COPD and emphsyema.