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miR-92a as a biomarker of diabetic retinopathy

miR-92a 作为糖尿病视网膜病变的生物标志物

基本信息

批准号：
10297984
负责人：
Ashay D Bhatwadekar
金额：
$ 47.2万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297984
关键词：
Algorithms Animal Model Background Diabetic Retinopathy Biological Markers Biological Models Biometry Blindness Blood Circulation Blood Vessels Blood capillaries Bone Marrow Bone Marrow Cells CD14 gene CD34 gene Cell physiology Cells Chimera organism Clinical Data Defect Development Diabetes Mellitus Diabetic Retinopathy Diagnosis Diagnostic Electroretinography Endothelial Cells Endothelium Exhibits Flow Cytometry Foundations Future Genomics Goals Grant Health Healthcare Human ITGA5 gene Impairment Individual Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 beta Lesion Longitudinal Studies Machine Learning Maps Messenger RNA MicroRNAs Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathology Patients Peripheral Phenotype Prognosis Proto-Oncogene Protein c-kit RNA Reporter Research Research Design Retina Retinal Diseases Rodent Rodent Model Role Sampling Series Severities Solid Surface System Systems Biology TLR6 gene Testing Up-Regulation Validity of Results Vascular Diseases Visual impairment autocrine biomarker discovery candidate marker cohort db/db mouse diabetic differential expression feature selection improved inflammatory marker insight migration non-diabetic novel marker overexpression paracrine potential biomarker predictive tools prognostic proliferative diabetic retinopathy repaired reparative capacity retinal damage standard of care tool transcriptome sequencing transcriptomics vascular injury

项目摘要

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.

糖尿病视网膜病变（DR）是一个全球性的问题，由于个体数量的惊人增长