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Overview

This chapter will introduce how mouse models have provided insights on the pathobiology and comorbidities of sickle cell disease (SCD), including vaso-occlusion and pain, which are the clinical hallmarks of SCD. Types of transgenic sickle mouse models will be presented, highlighting the correlation between hemoglobin pattern, anemia, and acute microcirculatory obstruction. Translational research using sickle mice has provided insights into the mechanisms underlying acute and chronic pain (Figure 7-1). Sickle mice provide a platform for preclinical testing of pharmacologic agents for pain and other comorbidities of SCD. Insights gained from mouse models into vascular complications of SCD, including retinopathy, nephropathy, pulmonary hypertension, priapism, and leg ulcers, are discussed. Limitations of mouse models are described, and future directions are presented.

FIGURE 7-1

Matings of SS mice provide evidence of the survival disadvantage of sickle cell disease. The proportion of SS and AS is 35:65, instead of the 50:50 for litters of AS and AA, respectively. Data from the lab of Kalpna Gupta.

Why Mice?

No animals have spontaneously developed sickle hemoglobin (HbS) and sickle vaso-occlusive pain. Although several species of deer have crescent-shaped red blood cells, their deformation occurs with oxygenation rather than with deoxygenation, and the deer do not have hemolytic anemia or vaso-occlusion, so they cannot serve as models for human SCD.1 Mice serve as an excellent model organism because of their relatively wide availability and ease of maintenance, cost-effectiveness, short life span, scope of genetic manipulations, and ability to model disease through diverse interventions including pharmacologic, cellular, surgical, and others. The inherent resilience of mice to manipulations provides flexibility in experimental design and consequent follow-up of disease processes. Mouse models have been developed to represent pathologic conditions by using genetic manipulations by gene insertions, deletions, or editing. Humanized mouse models are defined as “mice engrafted with functional human cells or tissues or expressing human transgenes.”2 These mice are a valuable asset because they afford an opportunity to intervene throughout the lifespan of the animal, which enables targeting the preventive strategies at the source before the sequelae of primary pathology leads to secondary complications. Mouse models of SCD have been developed using transgenic techniques. The goal was a mouse model for severe SCD that recapitulates extensive polymerization of HbS, hemolytic anemia, histologic and functional changes of vaso-occlusion, organ damage, and high mortality without treatment.

Types of Transgenic Sickle Mice

Overview and History

Milestones in the development of transgenic mouse models of SCD are summarized herein.3-5 The overall premise is that the extent of HbS expression correlates with the severity of hematologic and pathophysiologic complications in the mice, just as in human SCD. Thus, the biophysical principles for polymerization of deoxygenated (deoxy) HbS that were described in vitro (Chapters 1...

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