miR-92a as a biomarker of diabetic retinopathy

Diabetic retinopathy (DR) is a global problem due to an alarming increase in the number of individuals with
diabetes. The lack of an early diagnostic tool predicting retinal vascular health is a critical barrier to progress. To
this end, we have identified circulating angiogenic cells (CACs) as ideal reporter cells, which are most receptive
to changes of diabetic milieu and retinopathy. Our preliminary studies suggest that CACs map a distinct RNA
signature. We also found that a miRNA, miR-92a, is downregulated explicitly in CACs with DR, and its
overexpression in CACs of people with diabetes decreased pro-inflammatory markers, such as IL-1β and CD14,
emphasizing the importance of CACs for biomarker discovery of retinal vascular health. Our preliminary studies
using machine learning models could accurately predict DR providing us a stronger rationale for developing this
paradigm for our robust study design. Furthermore, using rodent models, we found a decrease in miR-92a in
lineage-Sca1+c-kit+ (LSK; mouse equivalent of CACs) parallels with an increase in acellular capillaries, and miR-
92a inhibition in LSKs triggered a stronger inflammatory response. Therefore, this proposal's overarching goal
is to study RNA (miRNA and mRNA) and inflammatory signature using a robust sequencing paradigm and
differential modeling in individuals with different severities of DR and animal models to gain insights into retinal
vascular health. Our central hypothesis is that RNA signature in CACs mirror DR severity, and miR-92a
decrease within CACs serves as a candidate biomarker. We propose the following specific aims to test our
hypothesis: Aim 1: To assess changes in RNA levels in CACs of patients with different severity of DR and
validate miR-92a as a candidate biomarker. Aim 2: Determine whether the miR-92a loss in bone marrow cells
is associated with the development of DR in rodents. We anticipate that our proposed studies will identify specific
mRNA and miRNA changes of DR severity and validate miR-92a as a novel biomarker for retinal vascular health.
Overall, our studies will help improve the standard of care of DR individuals by aiding in diagnosis, prognosis
and providing mechanistic insights for future therapies.

Grant Number: 5R01EY032080-05
NIH Institute/Center: NIH
Principal Investigator: Ashay Bhatwadekar