View clinical trials related to the Laboratory of Mitochondrial Biology and Metabolism

Cardiovascular Disease Discovery Protocol

Cardiovascular Disease Discovery Protocol (10-H-0126)

We propose to characterize the etiology and natural history of rare and uncommon diseases, both known and unknown that present with symptoms and signs associated with the risk of overt or potential cardiovascular dysfunction. We will also study rare genetic modifiers and identify novel disease mechanisms contributing to common cardiovascular diseases.  In so doing, we will expand our knowledge about these disorders and provide access to subjects of interest for research, teaching, and clinical experience.  Individual subjects seen under this protocol may initiate the establishment of specific disease-related protocols involving intensive natural history studies, disease discovery and potential innovative therapeutic studies. In addition to its role in investigating individuals who are of interest to the Cardiovascular and Pulmonary Branch (CPB) and the Center for Molecular Medicine (CMM) of the NHLBI, this protocol can provide a possible avenue for admitting subjects from other NIH programs such as the NIH Undiagnosed Diseases Program, the Center for Human Immunology Trans-Institute program or other NIH protocols where subjects exhibit cardiovascular features.

Pilot Study to Evaluate the Effect of Fasting on the NLRP3 Inflammasome

Pilot Study to Evaluate the Effect of Fasting on the NLRP3 Inflammasome (14-H-0103)

A caloric restricted diet has numerous health effects including the reduction in numerous cardiovascular disease risk factors. The cellular programs activated by caloric restriction are similarly turned on in preclinical studies in response to a 24-hour fast. We found that a beneficial effect of a 24-hour fasting blunted the activation of a component of the immune system, termed the NLRP3 inflammasome, which is associated with the development of diabetes and atherosclerosis. This clinical protocol was developed to study this inflammasome in human blood cells to evaluate whether the beneficial immune effects of fasting/caloric restriction are operational in humans. Blood samples to test the immune response were collected in subjects after a fixed caloric meal and in response to a 24-hour fast (water intake was not be restricted). The objective of this pilot study was to identify if these immune adaptive pathways can be activated in human subjects as a possible readout to test whether this pathway could be investigated as a therapeutic target to blunt/negate the inflammation associated with nutrient-excess associated diseases such as diabetes and/or atherosclerosis.

Pilot Study to Evaluate Fasting Effects on the Asthma Inflammasome

Pilot Study to Evaluate Fasting Effects on the Asthma Inflammasome (15-H-0136)

The NLRP3 inflammasome is part of the innate immune system that can be activated by atherosclerosis, gout and diabetes (sterile inflammation). As mitochondrial signaling can trigger the NLRP3 inflammasome, we initially proposed that fasting, via a nutrient-sensing mitochondrial program, would dampen this innate immune program. Our initial study showed that a 24-hour fasting blunts NLRP3 inflammasome activation in healthy young individuals. Interestingly, this inflammasome program has been implicated in the pathophysiology of bronchoreactivity linked to asthma and intermittent fasting has been found to reduce disease exacerbations in asthmatic patients. The objective of this protocol will extend our investigations, from what we are finding in young control normal volunteers, to enable us to investigate stable mild-moderate asthmatic subjects to determine whether fasting can blunt inflammasome activation and assess whether this transient nutrient-deprivation maneuver can improve airflow. Blood samples and pulmonary function testing to assay the immune response and bronchoreactivity will be performed in subjects in response to a 24-hour fast (water intake will not be restricted) followed by re-testing 2.5 hours after a fixed caloric meal. The objective of this pilot study is to identify if these immune adaptive pathways can be subdued in human subjects with a known inflammasome linked disease. Additionally, this study may enable us to identify a potential therapeutic pathway to blunt/negate inflammation associated with nutrient-excess associated bronchoreactivity of asthma.