PROJECT SUMMARY
Chronic obstructive pulmonary disease (COPD) affects 24 million US adults and over 1 billion people worldwide.
COPD patients often present with chronic hypercapnia (CH, elevated CO2 in the body), with severity of CH
increasing as the disease progresses. COPD is also marked by acute “attacks”, known as acute-on-chronic
exacerbations, further increasing the level of hypercapnia within the body. Some COPD patients demonstrate
tolerable, adaptive responses to the exacerbations, whereas others are prone to life-threatening severe
hypercapnia and potentially fatal cardiorespiratory dysfunction. The severity of CH may be an important factor
in setting the threshold of susceptibility to adaptive versus pathophysiologic responses. Indeed, our previous
findings have shown goats chronically exposed to mild CH (6% inspired CO2, InCO2) demonstrated adaptations
across multiple physiologic systems and tolerated further acute increases in InCO2 to 7 and 8% CO2. In contrast,
in a preliminary study on one goat, chronically increasing InCO2 from mild to moderate levels (8% InCO2),
resulted in pathophysiologic responses and the inability to compensate for acute further increases in InCO2 to
9% and 10%. The molecular underpinnings governing the protective/adaptive responses to chronic mild CH or
pathophysiologic/maladaptive responses to chronic moderate CH are unclear. Accordingly, the overall goal of
this proposal is to gain insight into CH-dependent molecular mechanisms which potentially underly both the
protective/adaptive (AIM 1) and pathophysiologic/maladaptive physiologic (AIM 2) responses to increased CO2
challenges. For AIM 1 I will expose adult goats to 14 days (d) of room air (Group 1) or mild CH (Group 2). For
AIM 2, I will expose goats to 7d of mild CH (6% CO2) followed by 7d of moderate CH (8% CO2) (Group 3). I will
measure physiological/pathophysiologic responses across multiple physiologic systems during steady-state
conditions and during acute CO2 challenges. Goats will be euthanized after these studies and I will extract tissue
from key brainstem cardiorespiratory nuclei and utilize bulk-tissue mRNA sequencing (btRNA-Seq) to identify
differentially expressed genes induced by both mild CH and moderate CH. I will use Ingenuity Pathway Analysis
to identify canonical pathways and functional gene networks that are significantly altered during mild CH (6%
CO2) alone, or 7d mild CH followed by 7d of moderate CH (8% CO2). Combining broad, unbiased techniques
(btRNA-Seq) and physiologic studies will provide novel insights into the molecular mechanisms regulating
cardiorespiratory control networks during CH. Further, results will yield information that will be critical in
understanding the effect CH has on the physiologic dysfunction observed in outpatient clinics and ICUs. The
training plan outlined in this proposal will provide me with the expertise needed to conduct physiologic
experiments, molecular biology techniques, and bioinformatic analyses required for the proposed studies.