# Enhancement of Human Immune System Development in Mouse Models > **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $230,250 ## Abstract Animal models are essential for studying biological processes underlying human health and diseases and developing safe and effective therapeutic approaches before human clinical trials. We dedicated our proposal to developing and characterizing new and significantly improved genetically modified animal models for human immune system establishment in mice. The conception of genetically engineered mice to engraft functional human immune systems opened a new horizon to study human-specific infections and associated multiorgan pathology. These models enable the successful engraftment of stem cells of non-fetal human tissue origin, including ex vivo engineered cells. Humanized mice are permissible to direct infection or challenges with wild- type human pathogens. Moreover, human cells isolated from experimental models became valuable for analyzing transcriptional and metabolic changes during infections and treatment. Thus, humanized mice have allowed researchers to address questions related to the treatment and prevention of important diseases like human immunodeficiency virus, hepatitis viruses (HIV/HBV/HDV/HCV), and newly emerging pathogens. Such models are directly applicable to study human health and diseases like human-specific infections, cancer immunology, transplantation of genetically modified human stem cells, and phenotypic characterization of various organ systems by omics approaches. We designed a new mouse background to avoid common cytokine gamma chain knockout and preserved secondary lymphoid organs for the efficient population with human immune cells. Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4, E4Bp4) transcription factor will be knocked out by CRISPR/Cas technology. By introducing human receptors and chemokines involved in the formation and growth of lymphoid tissues, we will improve the development of human adaptive immunity. To enable new strains of mice with the improved human immune system for the studies of human-specific hepatocytes infections, we will introduce fumarylacetoacetate hydrolase (Fah) gene knockout. Disruption of Fah gene on these new backgrounds will induce enzyme deficiency, currently regarded as the best model for human hepatocytes engraftment. Combining strain modifications will facilitate creating a dual humanized mouse model with immune system and liver to study human-specific infections, therapeutics development, and evaluation of vaccines. We will test our hypothesis by completing two specific aims: 1) to characterize the development and function of the human immune system in Nfil3/E4Bp4 knockout NOD/scid mice. Further improvement of human immune system functionality will be achieved by expressing the human lymphotoxin beta receptor, the chemokine CXCL13, and the thymic stromal lymphopoietin; 2) To disrupt Fah gene activity on NOD/scid-Nfil3-/- strain using CRISPR/Cas approaches. Advances in human immune system reproduction will fulfill increasing demands for developing improve... ## Key facts - **NIH application ID:** 10548100 - **Project number:** 1R21OD034048-01 - **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER - **Principal Investigator:** Santhi Gorantla - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $230,250 - **Award type:** 1 - **Project period:** 2022-07-01 → 2024-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10548100 ## Citation > US National Institutes of Health, RePORTER application 10548100, Enhancement of Human Immune System Development in Mouse Models (1R21OD034048-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10548100. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*