The Role of Circadian Rhythm Disruption in Polycystic Kidney Disease Progression
Abstract
This Discovery Award grant is within the Topic Area of Polycystic Kidney Disease (PKD). It falls under the Strategic Goal to improve the understanding of long-term complications and comorbidities of associated diseases and conditions. Background: Autosomal dominant Polycystic kidney disease (ADPKD) is a familial disease that affects the kidneys and livers of over 12.5 million people worldwide and an estimated 1 in 500 military personnel in the United States. It is usually diagnosed between the ages of 30 to 50, an age group that is trying to make a living, serve their country, raise a family, and have a social life. So how do sleepless nights and untimely eating due to working night shifts, training, or deployment, repeated time zone changes, crying babies, or nights out on the town, affect disease progression in ADPKD patients? We made a novel finding that the body’s timekeeper called the circadian clock is disrupted in the cystic kidneys of ADPKD mouse models and in human ADPKD kidneys. Chronic disruption of circadian rhythm is known to stimulate disease progression in various diseases, but its role in PKD is unknown. In the PKD kidneys, fluid filled cysts develop and grow over time, ultimately progressing to kidney failure. The objective of this grant is to determine the role of circadian rhythm disruption in ADPKD progression. Circadian rhythms are cyclical 24-hour rhythms that maintain equilibrium in the body by regulating our body functions. Each cell in our body has a clock, composed of clock proteins, which help to maintain these circadian rhythms. It is well known that disruptions to these circadian clock rhythms aggravate progression of some diseases such as diabetes, hypertension, various cancers, and Alzheimer’s disease. It is unclear if disruption of the circadian clock rhythms contributes to disease progression in ADPKD. Although no systematic study has been done to examine if individuals with ADPKD have circadian disruption, disturbed sleep, night-time urination, and non-dipping hypertension are known to occur in ADPKD patients, which indirectly suggests possibly circadian disruption. We have now obtained novel evidence that the circadian clock is disrupted in ADPKD kidneys. We found that an important clock protein called BMAL1 is abnormally expressed in the ADPKD kidneys. We hypothesize that the disrupted circadian rhythms due to abnormal expression of BMAL1 promotes disease progression in ADPKD kidneys. The study design involves two aims, which are based on strong preliminary data supporting our hypothesis and feasibility of the proposed studies. Aim 1 will inactivate BMAL1 in the early or later stages of disease progression in an ADPKD mouse model, and Aim 2 will determine the mechanism by which BMAL1 regulates ADPKD progression. Impact and Innovation: This would be the first study to determine the role of circadian disruption on ADPKD progression. This study is important because circadian disruption could be a risk factor that accelerates disease progression in ADPKD. Disease progression in individuals with ADPKD is not uniform, with rapid cyst growth starting anywhere between infancy to 80 years of age. If our hypothesis is correct, based on our preliminary data, we expect disruption of the circadian rhythm to accelerate ADPKD progression. We also expect to define the molecular mechanisms that accelerate ADPKD progression in mice with circadian disruption and the role of BMAL1. We expect to identify novel targets for treatment that could be beneficial for ADPKD patients. Innovation includes a novel hypothesis that the circadian rhythm is disrupted and is pathogenic in ADPKD kidneys and that reducing BMAL1 levels can slow or stop ADPKD progression. Our novel approach includes the use of an adult ADPKD mouse model, tissue-specific inactivation of BMAL1 gene and use of unbiased approaches to determine how BMAL1 regulates disease progression. This research will generate data that will form the fou
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310011
Entities
People
- Reena Rao
Organizations
- United States Army
- University of Kansas Medical Center