# Role of LDL receptor family members in protecting the vasculature

> **NIH NIH R35** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $772,500

## Abstract

The LDL-receptor related protein 1 (LRP1) is a highly efficient endocytic and a signal transducing receptor that
plays an important role in vascular development. By developing a mouse in which LRP1 was genetically
deleted in vascular smooth muscle cells (SMC), we have also discovered that LRP1 protects the vasculature
from the development of aneurysms. Currently, mechanisms by which this occurs are not well understood, but
our studies thus far reveal that LRP1 regulates matrix assembly, TGF signaling, and levels of protease
activity in the vessel wall. Defining the molecular mechanism by which LRP1 regulates these events is one
goal of this Outstanding Investigator Award. The significance of these studies are enhanced by the
identification of patients with aneurysmal disease harboring missense mutations in LRP1. Biochemical
characterization of the functional defects imposed by these mutant receptors will be critical to define the
mechanisms by which LRP1 regulates vessel wall homeostasis, and represents another major goal of our
studies. This will be accomplished by a the generation of mutant LRP1 substituted mice employing the
CRISPR/Cas9 system. LRP1 interacts with over 40 ligands with high affinity, and despite substantial effort,
very little information is available regarding the nature of the receptor/ligand complex. We also propose
strategies to solve this problem using the latest technological advances in structural biology. Closely related in
structure to LRP1 is LRP1B, another receptor that is abundant in SMC and regulates their migration and
proliferation by unknown mechanisms. We propose genetic, proteomic and RNA-seq analysis to identify
mechanisms by which this receptor regulates SMC growth. Together, the studies will define the mechanisms
by which LDL receptor family members protect the vasculature from disease and may identify novel
therapeutic approaches for patients harboring LRP1 missense mutations.

## Key facts

- **NIH application ID:** 9844978
- **Project number:** 5R35HL135743-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Dudley K. Strickland
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $772,500
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844978

## Citation

> US National Institutes of Health, RePORTER application 9844978, Role of LDL receptor family members in protecting the vasculature (5R35HL135743-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844978. Licensed CC0.

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