R35HL161244

Precision Nanomedicine Targeting Novel Endothelial Mechano-Sensing Mechanisms - Project Summary

Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease, but targeting disease-causing mechano-sensing pathways remains extremely challenging. For instance, atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed blood flow activates the endothelium. However, current atherosclerosis therapies mainly target systematic risk factors, but not the vasculature itself. This underscores the significance and unique opportunity to identify and target novel mechano-sensitive mechanisms in activated endothelium subjected to disturbed flow.

This proposal aims to first delineate novel endothelial mechano-sensing mechanisms and, moreover, devise innovative precision nanomedicine approaches targeting these disease-causing mechano-sensitive pathways. This R35 mechanism will provide us a unique opportunity to synergistically combine our efforts in endothelial biology (R01 HL136765) and vascular nanomedicine (R01 HL138223), testing paradigm shift hypotheses related to endothelial mechanotransduction and addressing an unmet medical need in vascular therapies.

Specifically, seminal work from us and colleagues, along with our unpublished data, identified three new layers of molecular controls of endothelial mechano-transduction: epigenome (DNA chemical modification), epi-transcriptome (mRNA chemical modifications), and metabolism (glycolysis and oxidative phosphorylation). The overall goals of this project are to 1) identify novel regulators governing the endothelial epigenomic, epi-transcriptomic, and metabolic responses to blood flow, and 2) engineer innovative nanoparticles which target each of these pathways, treating vascular complications in vivo.

The scientific premise is that innovative nanoparticles can effectively deliver therapeutic nucleotides targeting these mechano-sensitive pathways in activated endothelium. This proposal addresses a significant knowledge gap in endothelial biology and an uncharted territory in vascular medicine, research directions being pursued by only a small number of laboratories worldwide. Our team has laid much of the groundwork in developing multidisciplinary knowledge, technologies, and animal models necessary to investigate new endothelial mechanotransduction paradigms and, moreover, devise precision nanomedicine strategies for future tailor-made vascular therapies.

Successful completion of the proposal will establish a proof of concept of targeted nanomedicine in vascular wall-based therapies. The proposed studies should further preclinical development and eventual clinical testing of new therapeutic strategies to treat vascular diseases.

University Of Chicago

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Chicago, Illinois 606375418 United States

Single Zip Code

NHLBI Emerging Investigator Award (EIA) (R35 Clinical Trial Optional) (RFA-HL-20-012)

Amendment Since initial award the total obligations have increased 297% from $811,040 to $3,222,128.