# Artery biomechanics and vascular damage in sickle cell disease

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $564,117

## Abstract

Sickle cell disease (SCD) affects approximately 100,000 people in the U.S. but 300,000 babies are born with
SCD every year globally. Currently few pharmaceutical options are available as a therapy, and life expectancy
is still low for these individuals. Consequences of accelerated arterial damage include a 221-fold increased risk
of strokes in children and then increased risk of hemorrhagic strokes during the third decade of life. Elastic lamina
fragmentation were hallmarks identified in autopsy specimens of children with SCD, but underlying mechanisms
are unclear and therefore cannot be prevented. Cysteine cathepsins are powerful proteases implicated in elastin
and collagen degradation in cardiovascular disease (i.e. atherosclerosis). It was recently published by the PIs
that cathepsins are similarly active in a transgenic sickle cell mouse model, and inhibition of JNK signaling
blocked this as well as pathological arterial remodeling and biomechanical consequences. The long term goal
is to identify novel therapeutic targets to inhibit proteolytic activity and cellular mechanisms that cause
accelerated elastin and collagen degradation and pathological biomechanics in arteries of children and adults
with SCD, and determine accumulated damage as they age. The objective is to investigate cathepsin-mediated
arteriopathy and pathological biomechanical changes in large arteries due to SCD causing irreparable damage,
and if curative bone marrow therapies prevent further arterial remodeling. Based on preliminary data and
published studies, the central hypothesis is that cathepsin-mediated elastinolytic and collagenolytic activity in
large arteries is JNK-dependent and downstream of the chronic inflammation (TNFα and monocytosis) caused
by sickle cell disease. This hypothesis will be tested according to the following aims: Aim 1. To determine roles
of cathepsin K in elastic lamina and collagen degradation by SCD as mice age and accumulate damage to
arteries using a new mouse model that was generated by the investigators that is transgenic for sickle cell
disease but null for cathepsin K. Aim 2. To improve JNK inhibition strategies that downregulate cathepsin
expression and protect arterial integrity. Aim 3. To determine efficacy of curative BMT in preventing further
arterial damage, and the need for further pharmaceutical interventions. This work is significant because its
success will identify mechanisms to preserve integrity of arteries that undergo progressive damage over a
lifetime with SCD even after curative bone marrow transplants. Innovative aspects include: 1) Studying arterial
remodeling complications of SCD as opposed to the deoxygenated post-capillary venules and microcirculation
that has dominated the field; 2) decomposing collagen degradation from elastin fragmentation and impact on
arterial mechanics in SCD; and 3) identifying critical ages by which maintenance of vascular integrity may offer
improved chance of preventing future cardiovasc...

## Key facts

- **NIH application ID:** 10606485
- **Project number:** 5R01HL158159-03
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Edward A. Botchwey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $564,117
- **Award type:** 5
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10606485

## Citation

> US National Institutes of Health, RePORTER application 10606485, Artery biomechanics and vascular damage in sickle cell disease (5R01HL158159-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10606485. Licensed CC0.

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