# Humanized Mouse Avatars for T1D

> **NIH NIH U01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $1,005,973

## Abstract

PROJECT SUMMARY / ABSTRACT
To date, studies of human type 1 diabetes (T1D) have failed to provide a mechanistic understanding of the
underlying causes of the disease, largely because patients must be analyzed long after initiation of the
autoimmune attack. Our ignorance of the key molecules and cells mediating the initiation and progression of
human T1D may well underlie the paucity of significant new therapeutic interventions. This renewal proposal
addresses the stated goal of RFA-DK-18-013 that “CMAI supports resource development projects that are
primarily focused on the reagents and model systems needed for mechanistic study of human T1D.” Our
Scientific Premise is that human T1D beta cells and immune cells transplanted into optimized
immunodeficient mice (OPTI-MICE) will provide tractable model systems to study human T1D. We
propose short term (Aim 1) and long term (Aim 2) goals. Aim 1 will develop an effector phase model of
T1D in OPTI-MICE. Our team has already assembled the 3 key components that are required to develop an
effector model of T1D: 1) Appropriate OPTI-MICE as recipients; 2) autoreactive T cells, lines, clones and iPS-
derived T cells from T1D donors; 3) autologous human iPS cell-derived (SC)- cells. We have developed NSG
mice deficient in MHC class I and II that do not develop GVHD when engrafted with functional human T cells
for this aim. We have also recruited Dr. Sally Kent, an expert in islet autoreactive T cell cloning, to provide
T1D autoreactive T cell lines and clones from consented T1D patients. Aim 2 will reconstruct human T1D in
OPTI-MICE using cells derived from T1D iPS cells. These iPS cells will be used to produce the three key
cell types: hematopoietic stem cells (HSC) that will generate immune systems, thymic epithelial cells (TEC),
and β-cells, all integral to the pathology of T1D. These cells will be derived through the use of directed
differentiation and reprogramming strategies. We have been successful in generating functional human β cells
from human control and T1D patient iPS cells, providing a standardized and reproducible source of β cells for
our studies. We have successfully performed directed differentiation of human ES cells to generate HSCs, and
will use similar approachs for directed differentiation of iPS cells into HSCs. Functional human TEC will also be
generated using directed differentiation protocols similar to those used to achieve fully differentiated human β
cells. Each cell type will be subjected to rigorous analysis in vitro and in vivo to ensure full functionality.
Differentiated β-cells, TECs, and immune cells derived from T1D donors will be co-transplanted into OPTI-
MICE specifically optimized to enhance T cell, SC-β cell, SC-HSC, and SC-TEC cell engraftment and function
allowing reconstitution of an individual patient's disease in an animal model. These new models of human
diabetes will permit detailed observation, manipulation, and analysis of T1D, enabling us to determine the ...

## Key facts

- **NIH application ID:** 10412982
- **Project number:** 5U01DK104218-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michael Allen Brehm
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,005,973
- **Award type:** 5
- **Project period:** 2014-09-25 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412982

## Citation

> US National Institutes of Health, RePORTER application 10412982, Humanized Mouse Avatars for T1D (5U01DK104218-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412982. Licensed CC0.

---

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