# Conformation-dependent regulation of KRIT1 and the CCM complex

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

Summary/Abstract
The regulation of blood vessel barrier function is one of the most important functions of the vascular network,
and one of the first functions to be affected by the disease state. Despite the fact that most cardiovascular
diseases affect the permeability of the blood vessel wall, our knowledge of how vascular permeability is
regulated under normal conditions remains incomplete. The CCM protein complex, containing the scaffolding
proteins KRIT1, CCM2, and PDCD10/CCM3, is critical for the stability of endothelial cell-cell contacts and
regulation of vascular permeability in vivo. However, we still know relatively little about how these proteins are
regulated in a normal functioning cell, or how this complex actually stabilizes cell-cell contacts. Preliminary
data indicate that the localization of KRIT1 at endothelial adherens junctions (AJ) is essential to the proper
functioning of the entire CCM complex, and that this localization is controlled by the conformation of KRIT1 and
by the interaction of KRIT1 with its known binding partners. We hypothesize that the trafficking of KRIT1 to
intracellular sites controls the ability of the CCM complex to regulate permeability in endothelial cells.
Therefore, we propose to use several advanced imaging and biochemical approaches to determine the
respective conformation and binding interactions of KRIT1 in three subcellular locations: the plasma
membrane, the cytoplasm, and the nucleus. This information will be used in conjunction with functional assays
to construct a model of KRIT1/CCM signaling within an intact endothelial monolayer. This information will be
critical for future drug development targeting the CCM complex and will significantly increase our
understanding of vascular homeostasis.

## Key facts

- **NIH application ID:** 9855071
- **Project number:** 5R01HL141131-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Angela J Glading
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855071

## Citation

> US National Institutes of Health, RePORTER application 9855071, Conformation-dependent regulation of KRIT1 and the CCM complex (5R01HL141131-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855071. Licensed CC0.

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