Selected Grantee Publications
Systematic Ocular Phenotyping of 8,707 Knockout Mouse Lines Identifies Genes Associated With Abnormal Corneal Phenotypes
Vo et al., BMC Genomics. 2025.
https://pubmed.ncbi.nlm.nih.gov/39833678
Corneal dysmorphologies (CDs) are a group of acquired but predominantly genetically inherited eye disorders that cause progressive vision loss and can be associated with systemic abnormalities. This study aimed to identify candidate CD genes in humans by looking at knockout mice with targeted deletions of orthologous genes that exhibited statistically significant corneal abnormalities. Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes; 176 (83%) genes have not been implicated previously in CD. Bioinformatic analyses implicated candidate genes in several signaling pathways (e.g., integrin signaling pathway, cytoskeletal regulation by Rho GTPase, FAS signaling pathway), which are potential therapeutic targets. Supported by ORIP (U42OD011175, R03OD032622, UM1OD023221), NEI, and NHGRI.
Profiling Development of Abdominal Organs in the Pig
Gabriel et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-19960-5
The pig is a model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Moreover, advances in CRISPR gene editing have made genetically engineered pigs a viable model for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects. Here, the authors describe normal development of the pig abdominal system (i.e., kidney, liver, pancreas, spleen, adrenal glands, bowel, gonads) and compare them with congenital defects that can arise in gene-edited SAP130 mutant pigs. This atlas and the methods described here can be used as tools for identifying developmental pathologies of the abdominal organs in the pig at different stages of development. Supported by ORIP (U42OD011140), NHLBI, NIAID, NIBIB, NICHD, and NINDS.
Identification of Basp1 as a Novel Angiogenesis-regulating Gene by Multi-Model System Studies
Khajavi et al., FASEB Journal. 2021.
https://pubmed.ncbi.nlm.nih.gov/33899275/
The authors previously used genetic diversity in inbred mouse strains to identify quantitative trait loci (QTLs) responsible for differences in angiogenic response. Employing a mouse genome-wide association study (GWAS) approach, the region on chromosome 15 containing Basp1 was identified as being significantly associated with angiogenesis in inbred strains. To investigate its role in vivo, they knocked out basp1 in transgenic kdrl:zsGreen zebrafish embryos using a widely adopted CRISPR-Cas9 system. They further showed that basp1 promotes angiogenesis by upregulating β-catenin gene and the Dll4/Notch1 signaling pathway. These results provide the first in vivo evidence to indicate the role of basp1 as an angiogenesis-regulating gene. Supported by ORIP (R24OD017870) and NEI.
Establishing an Immunocompromised Porcine Model of Human Cancer for Novel Therapy Development with Pancreatic Adenocarcinoma and Irreversible Electroporation
Hendricks-Wenger et al., Scientific Reports. 2021.
https://pubmed.ncbi.nlm.nih.gov/33828203/
Efficacious interventions to treat pancreatic cancer lack a preclinical model to recapitulate patients' anatomy and physiology. The authors developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. These pigs were successfully generated using on-demand genetic modifications in embryos. Human Panc01 cells injected into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. This model will be useful to bridge the gap of translating therapies from the bench to clinical application. Supported by ORIP (R21OD027062), NIBIB, and NCI.