ADAR2 and Adipose Dysfunction in Aging

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 DESCRIPTION (provided by applicant): Aging is a complex process that involves continuous accumulation of cellular damage. Interventions to prevent these damages will improve aging related pathologies. Adipose dysfunction increases with age, which dramatically alters fat mass, redistribution and function, leading to metabolic imbalance and increased risk to cardiometabolic diseases. Continuous turnover of adipose cells and thus recruitment of new pre-adipocytes (or adipose derived stem cells) and adipocytes is essential in maintaining adipose mass and function. Our recent studies showed age-dependent dysfunction in fat depots attributed to inability of pre-adipocytes to differentiate into adipocytes with aging due to de-regulation of adipogenic microRNAs (miRNAs). Pre-adipocyte differentiation is regulated by both genetic and epigenetic mechanisms. Understanding this phenomenon is important, since it will help (i) to better understand the relationship between the aging phenotype and adipose dysfunction and (ii) identify targets to treat or prevent cardiometabolic diseases that are associated with aging. Adenosine Deaminase acting on RNAs (ADAR) family of enzymes are key in post-transcriptional regulation and essential for RNA and protein diversity through RNA editing. Loss of ADARs resulted in increased mortality in US centenarians, increased risk to age-associated neurological diseases such as dementia and certain cancers. Loss of ADAR also resulted in increased obesity and insulin resistance. ADARs are currently explored as a good therapeutic target for certain neurological diseases and cancer. We hypothesize a loss of ADARs with aging plays a role in the observed age-mediated adipose dysfunction. We will test this hypothesis by proposing three aims. Our studies will use pre-adipocytes isolated from the visceral fat of young Fischer 344 x Brown Norway hybrid rats (6mo) compared to aged FBN rats (14mo, 24mo, 30mo). These rats are similar to humans and develop adiposity and insulin resistance with increasing age. AIM 1: To demonstrate the role for ADARs in the miRNA regulation of adipose function in aging. The goal of this aim is to investigate if ADAR expression and activity are altered with aging and it plays a role in the impairment of adipogenic miRNA and adipose function. AIM 2: To demonstrate that ADAR regulates adipogenic miRNA targets with aging: The goal of this aim is to determine if ADARs regulate the mRNA targets of adipogenic miRNA (miR-143), adipogenic/osteogenic miRNA (miR-204) and osteogenic miRNA (miR-22). AIM 3: To demonstrate that modulation of ADAR levels in aging pre-adipocytes will improve adipocyte function. The goal of this aim is to demonstrate the role of ADAR-mediated RNA editing pathways in pre-adipocyte dysfunction with aging by using gain or loss of function approaches for modulating ADAR levels. Our proposed studies are novel and innovative and will, for the first time, explore the role of RNA editing in adipose biology and its relation to metabolic dysfunction and identify novel therapeutic targets. These studies will provide excellent research experience and opportunity for Marshall University undergraduates in the biomedical field.