# Animal Models Core

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $306,306

## Abstract

Project Summary/Abstract
Alpha-1 antitrypsin (AAT) is the second most abundant serum protein with circulating levels of 570-1500
mcg/ml. It is a multi-functional anti-protease and anti-inflammatory protein whose prototypic function is to
neutralize neutrophil elastase, protecting the interstitial elastin in the lung parenchyma from degradation. This
was first described as a genetic syndrome of emphysema associated with the deficiency of AAT five decades
ago. The glu342lys (PiZ) mutation of AAT is remarkably common in Northern Europe, with a carrier frequency
in several of those nations exceeding 5%. In North America the carrier frequency is approximately 4%, making
AAT deficiency among the most common genetic disorders. In the homozygous state (PiZZ), AAT deficiency
is also associated with a liver disease that appears to be due to retention of Z-AAT polymers and aggregates
within hepatocytes, which are the cells responsible for the production of the bulk of AAT in the serum.
Animal models play an important role in the understanding of the pathogenesis of chronic obstructive
pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD). The latter being served by the PIZ
mouse that accumulates AAT globules in the liver and goes on to develop liver disease. There are many
abundant examples in the literature of transgenic mice that have contributed to the understanding of COPD,
but none so far has been able to model lung disease as a consequence of AATD. Previous gene-targeting
studies aimed at the serpina1 gene and its isoforms in mice have failed. This failure is mainly due to the
complexity of the locus, in which a gene amplification event in mice results in 6 highly conserved isoforms of
the gene, of which, depending on the stain, 3 to 5 copies are expressed. To the best of our knowledge our
laboratory has created the first complete mouse knockout of alpha-1 antitrypsin. The core will make these mice
available to the various projects of this grant along with an un-paralleled variety of other mouse models of
which 3 are unique to this core. The core will also be phenotyping and creating new mouse lines. This will be
accomplished in the following three aims. Aim 1 will characterize the biochemical and physiological phenotype
of the AAT knockout mice and their utility to predict gene augmentation efficacy. Aim 2 will focus on generating
a more physiologically relevant mouse models for testing genome editing of Z-AAT alleles as well as an AAT
KO mouse in which to investigate immune responses to rAAV-AAT augmentation vectors. Finally, aim 3 will
optimize the PiZ-NSG mouse for human liver xeno-engraftment.

## Key facts

- **NIH application ID:** 9935127
- **Project number:** 5P01HL131471-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Christian Mueller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,306
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935127

## Citation

> US National Institutes of Health, RePORTER application 9935127, Animal Models Core (5P01HL131471-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935127. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*