# AIBP therapy

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $930,000

## Abstract

Project Summary
 This proposal describes a research program to establish mechanistic foundations and conduct preclinical
studies toward AIBP therapy. We discovered that the secreted apoA-I binding protein (AIBP) accelerates
cholesterol efflux from endothelial cells (EC) and macrophages and targets HDL to TLR4-occupied lipid rafts.
Resulting targeted cholesterol removal from the plasma membrane and reduction of lipid rafts leads to reduced
TLR4-mediated inflammatory responses. The significance of this discovery is in the widespread character of
the AIBP/lipid rafts mechanism of anti-inflammatory regulation, which can be relevant to many inflammatory
conditions. The translational importance of our findings arises from the extracellular mode of AIBP regulation
and thus the possibility of recombinant protein infusion or inhalation. Considering an atheroprotective function
of AIBP, the integrity and the normal physiological function of EC are critically important for maintaining a
healthy vascular wall. We have strong preliminary data showing that AIBP facilitates HDL-mediated cholesterol
efflux from EC, reduces EC expression of inflammatory genes and reduces monocyte adhesion to EC. These
results suggest a strong impetus to pursue AIBP atheroprotective therapeutic applications. Cardiac reperfusion
after an acute myocardial infarction (MI), or ischemia/reperfusion (I/R), contributes to myocardial injury, which
generates subsequent inflammatory cascade, which in turn perpetuates cardiac damage. Innate immune
receptors in general and TLR4 in particular critically contribute to I/R damage. Reducing inflammatory
responses to I/R via increased removal of cholesterol from cardiomyocytes and vascular cells will be
particularly important for post-MI patients. We posit that infusions of AIBP, alone or in combination with
reconstituted HDL, will provide benefit to post-MI patients' health because AIBP specifically targets HDL to
inflammatory cells. The extracellular mechanism of AIBP action also opens the possibility of its local
administration in lung inflammation. Acute respiratory distress syndrome (ARDS) often results in death of those
afflicted by its most severe subset due to the lack of effective therapies. Excessive inflammatory responses,
including recruitment of neutrophils, secretion of cytokines and the development of alveolar edema,
characterize ARDS in humans and rodents. We have shown in a mouse model of ARDS that nebulized AIBP
significantly reduces lung inflammation. Our research program will focus on understanding basic anti-
inflammatory mechanisms of AIBP and will use preclinical animal models, including mouse and zebrafish, and
patients' blood samples to evaluate the potential of AIBP therapy in atheroprotection and in treatment of post-
MI and ARDS patients.

## Key facts

- **NIH application ID:** 9858442
- **Project number:** 5R35HL135737-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Yury Miller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $930,000
- **Award type:** 5
- **Project period:** 2017-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858442

## Citation

> US National Institutes of Health, RePORTER application 9858442, AIBP therapy (5R35HL135737-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9858442. Licensed CC0.

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