Overview

The manifestations of CF begin in infancy and the management of this disease becomes a life-long focus for patients and their families. Since the establishment of CF newborn screening, new patients are being identified at a very young age – young enough to greatly benefit from a new model of healthcare for CF that predicts disease progression, monitors for its symptoms, and approaches the disease and its physiologic consequences prospectively, rather than waiting for symptoms to arise.

Progressive lung disease is evident in two temporal phases: a slow decline in lung function in the sub-acute phase, punctuated by APEs in the acute phase. During an APE, the ecology of the lung is driven out of balance, most likely due to enhanced oxidative stress associated with an increase in bacterial burden and consequential increase in neutrophil invasion and activation, leading to progressive lung destruction. The frequency of APEs depends upon several factors including: age, CFTR genotype, socio-economic status, exposure to inciting agents such as respiratory viruses, cigarette smoke, and other environmental pollutants, and, most importantly, vigilance and aggressiveness of response on the part of the adult patient or the parent of a child with CF. The frequency of APEs is the most important determinant of mortality in CF. We hypothesize that the events leading to an APE have been underway for some time before symptoms appear; if we could predict an APE, the available therapies would be more efficacious. What the CF clinician needs is a way to recognize an oncoming APE before the symptoms appear. Therefore, our research in APEs aims:

• To undertake a comprehensive study to identify biomarkers of acute disease progression that appear before the patient develops symptoms
• To mine the data using statistical modeling and systems biology approaches to identify the set of biomarkers with the strongest predictive value for an APE.
• The long-term goal is to set the stage for the development of a home device to measure these biomarkers, allowing clinicians to predict an oncoming APE, thus enabling aggressive treatment.

CF-related diabetes (CFRD) is one of the most important co-morbidities in CF. CFRD appears in young children as impaired glucose tolerance, which is found in ~40% of CF toddlers. The prevalence of CFRD increases with age and reaches staggeringly high proportions with 20% of teens and 50% of adults having CFRD. The health issues related to CFRD are devastating, as CFRD is associated with a more rapid decline in lung function, worse nutrition, more frequent hospitalization, and increased mortality compared to CF individuals without CFRD. Although CFRD shares some features of both type 1 and type 2 diabetes, it is a distinct disease entity. Patients with CFRD have a significantly higher mortality than CF patients without diabetes. Death in CFRD is due to accelerated progression of lung disease and respiratory failure, not diabetes-induced vascular disease; however, the mechanism(s) whereby CFRD worsens CF lung disease remain unknown. Of equal concern is the extreme paucity of work that addresses the mechanisms involved in the development of CFRD, leaving the question of factors that promote insulin insufficiency and consequent CFRD largely unanswered. Therefore, our research focus in CFRD aims:

• To determine the mechanism whereby mutations in CFTR lead to the development of CF diabetes.
• To determine the mechanisms whereby the development of CF diabetes leads to acceleration in lung decline and premature death.
• To determine whether the systemic redox imbalance associated with CF hastens the damage to the pancreas that leads to insulin insufficiency.
• To test novel therapeutic approaches to overcome the defects that link systemic hyperglycemia to accelerated pulmonary decline.

Three Scientific Cores are supported by the CF@LANTA RDP Center (see figure above): (1) Clinical and Translational Core; (2) Experimental Models Support Core; and (3) CF Analytics Core. Each of these Cores leverages capabilities established within CF-AIR, and also leverages existing strengths at Emory and Georgia Tech in systems biology approaches to complex diseases. The RDP Center also supports an Administrative and Enrichment program, a Pilot & Feasibility program, and a Research Training Core (for more detail on the educational components please see here).

The studies proposed and underway in our team extend from molecules to tissues to humans. Center investigators will use state-of-the-art approaches to study patients and patient-derived samples to identify the changes in airway function with respect to inflammation and redox imbalance that accompany development of CFRD and progression of disease via APEs, and will use experimental systems to test mechanistic hypotheses to integrate these results in the context of patient data on disease progression. This resultant new understanding will be translated back to the patient, taking advantage of the Clinical and Translational Core and the leaders of the clinical research team at Emory and Children’s.