SnoRNAs and RNA Modifications in Cardiovascular Diseases

The Holley Laboratory is focused on the role of non-coding RNA (ncRNA) and post-transcriptional RNA modifications in cardiovascular health and disease, with a special emphasis on snoRNAs (small nucleolar RNAs).

SnoRNAs are canonically known to guide the post-transcriptional modification of other RNAs, with rRNA and snRNA being the primary targets.  Our lab has now discovered that box C/D snoRNAs can target mRNAs for modification by 2′-O-methylation, regulating both the expression and translation of the target mRNA.

Dr. Holley’s research has helped to uncover a novel biologic role for the Rpl13a snoRNAs in the regulation of reactive oxygen species (ROS) and oxidative stress.  These four snoRNAs (SNORD32A, SNORD33, SNORD34, and SNORD35A) have a critical role in the oxidative stress response to a variety of stimuli, including saturated fatty acids, lipopolysaccharide, doxorubicin, and hydrogen peroxide. Ongoing work suggests that these snoRNAs fundamentally regulate aspects of mitochondrial metabolism, though the exact molecular mechanism is still unclear.

The role of these snoRNAs in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure is an active area of research. We have found that genetic loss of Rpl13a snoRNAs reduces atherosclerosis (athero), and we have developed antisense oligonucleotides (ASOs) that reduce athero in mouse models. We have a patent pending and are actively working to develop these ASOs as potential RNA therapeutics for patients.

HLA Sensitization, Primary Graft Dysfunction, and Antibody-Mediated Rejection in Heart Transplantation

The pre-existing presence of HLA antibodies against a donor heart can prevent successful heart transplantation, and the development of de novo antibodies after transplant can lead to antibody-mediated rejection (AMR). Dr. Holley is involved in translational and clinical efforts to desensitize patients prior to heart transplantation and to effectively treat AMR. Primary graft dysfunction (PGD) is the failure of a transplanted heart in the immediate post-operative period, without evidence of cellular or antibody-mediated rejection. Little is known about this entity, so Dr. Holley is leading translational efforts to define the underlying etiology of PGD, which may be related to inflammation that is unrelated to HLA-dependent cellular or antibody-mediated rejection.