Tissue-Specific and Diurnal Pattern of Gene Expression in a Nonhuman Primate
Abstract
Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Areas: Diabetes and Sleep Disorders Disruption to the natural daily rhythm in sleep-wake and eating-fasting routines is a necessity for military personnel during deployment. Such habits persist even when military personnel return to civilian life. Acute or chronic disruption of daily rhythms predisposes individuals to a range of discomfort and diseases including insomnia, compromised performance, depression, anxiety, post-traumatic stress disorder, heartburn, prediabetes, diabetes, cardiovascular diseases, cancer, and dementia. Progress in basic science research in circadian rhythm primarily done in insects and rodents has revealed that normal health is supported by daily rhythms in gene activities that produce rhythms in hormones, enzymes, steroids, and metabolites or biomolecules. The model organisms traditionally used for circadian rhythm research cannot always model human health and diseases. Insects have very rudimentary nervous system, do not maintain their core body temperature, and lack many organs and brain regions of humans. Rodents are active at night, can sleep under light, lack consolidated sleep, eat randomly, and most strains do not produce melatonin – important traits that show daily rhythms in humans. On the other hand, it is impossible to collect serial tissue samples to test which genes in humans show daily rhythms in different brain regions, hormone glands, guts, liver, lungs, pancreas, etc. This gap between rodent and human models of daily rhythm must be filled in order to develop an accurate and complete understanding of how daily activation of genes and biomolecules shape our overall health. This funding request will fill the inherent gaps by producing a fine timeline map of all genes and metabolites in dozens of tissues and brain regions from a nonhuman primate – the baboon. The tissue samples for this project have already been carefully collected from the International Primate Resource Center in Nairobi, Kenya following institutional, national, and international protocols and approvals from relevant regulatory agencies. The samples have also been validated with preliminary gene expression experiments that revealed that up to 82% of protein-coding genes in baboons show daily rhythm in different organs. This surprising result indicated that there is a hidden time-code to our genome. Obtaining a detailed picture of the time-based activation of genes and metabolites will give us a thorough understanding of how daily rhythms in humans originate. These findings will give us important clues about the consequences that occur when such rhythms are disrupted by shiftwork and ultimately lead to diabetes, cardiovascular diseases, and dementia. This proposal will use the expertise of Satchidananda Panda, PhD, in circadian rhythm research and of Jeffrey Rogers, PhD, in comparative primate genomics and genome sequencing. Together, they will apply their complementary skills to analyze these precious samples from baboons. They will use state-of-the-art genome sequencing instruments to determine which genes are turned on at what time in different organs. Next, they will perform analyses consisting of an innovative combination of genome sequencing and gene expression to determine how individual differences between baboons contributes to differences in the activation of different genes in multiple organs. Further, the investigators will examine very minor differences in the sequences of individual baboon genes that might have been inherited from their mother and father, and they will test whether there is a gender or parental bias in which copy of the genes are turned on in different organs. In a parallel approach, the collected tissue will be examined by using advanced metabolite analyses to identify thousands of biomolecules at different times of the day. Finally, both gene activation and metabolite abundance will be analyzed
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810646
Entities
People
- Jeffrey Rogers
Organizations
- Baylor College of Medicine
- United States Army