Positions
- Associate Professor
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Molecular and Human Genetics
Baylor College of Medicine
- Member
-
Genetics & Genomics Graduate Program
Baylor College of Medicine
- Member
-
Development, Disease Models & Therapeutics Graduate Program
Baylor College of Medicine
- Director
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Center for Precision Medicine Models
Baylor College of Medicine
- Academic Director
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Genetically Engineered Rodent Models (GERM) Core
Baylor College of Medicine
- Co-Leader, Advanced in Vivo Cancer Models Shared Resource
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
- Member
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
- Vice-Chair
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International Mouse Phenotyping Consortium
Addresses
- Department of Molecular and Human Genetics (Office)
-
Baylor College of Medicine
Houston, TX 77030
United States
Education
- BS from University Of New Hampshire
- 01/1998 - Durham, NH United States
- PhD from Pennsylvania State University
- 01/2004 - Hershey, PA United States
- Post-Doctoral Fellowship at Case Western Reserve University
- 01/2010 - Cleveland, OH United States
Professional Interests
- Germ cell developement, infertility, and cancer
- Mammalian genetics
- Mouse models of human diseases
- Genome editing technologies
Professional Statement
In my laboratory we use mouse genetics, genomics and genome editing technologies to catalog gene function and contribution to human disease. Ongoing research includes:Characterizing genes and developmental pathways that contribute to testicular germ cell tumors (TGCTs). Germ cells arise during embryogenesis as pluripotent-like primordial germ cells (PGCs) that differentiate into mature gametes and ultimately the cells and tissues of an adult organism. Defects during male germ cell development can lead to the formation of TGCTs. In 129 mice, TGCTs arise during embryogenesis as foci of pluripotent embryonal carcinoma cells (EC cells), which differentiate to form teratomas. During embryogenesis, male germ cells normally enter mitotic arrest until after birth and female germ cells initiate the meiotic program, both of which are accompanied by down-regulation of pluripotency. We have identified a defect in this developmental switch as the cause of TGCT initiation. In TGCT susceptible gonads, XY germ cells do not enter mitotic arrest, delay expression of male germ cell differentiation genes, and continue to express core pluripotency factors. Ongoing studies are using genome editing in mice, developmental biology approaches, and single-cell RNA sequencing to (1) characterize mechanisms by which male germ cell sex specification is delayed, (2) test the contribution of a shift in pluripotent states to germ cell transformation into EC cells, (3) functionalize TGCT susceptibility loci identify in human genome-wide association studies, and (4) explore environmental contributions to TGCT risk.
Determining the mechanisms by which gene loss-of-function contributes to infertility. The Knockout Mouse Phenotyping Program (KOMP2), as a part of the International Mouse Phenotyping Consortium (IMPC) has established an infrastructure for high-throughput generation of null alleles and broad-based, adult and embryo phenotyping of knockout mouse lines. To date, 6.5% of the mouse lines characterized by the IMPC demonstrate male and/or female infertility with many novel infertility genes being identified. Ongoing studies are focused on these novel infertility genes with the goals of (1) understanding the cellular and molecular mechanisms by which loss-of-function mutations in these genes contribute to infertility and (2) determining whether these genes are potential targets for novel birth control options.
Characterizing gene and variant contribution to Mendelian diseases. Up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or the clinical significance of identified variants remains unclear. Precision model organisms are important tools aiding in the interpretation of these variants and are critical for testing therapeutic paradigms. The BCM Center for Precision Medicine Models supports local, national, and international programs and individual researchers in the development of precision fly and mouse that will end the diagnostic odyssey of patients with undiagnosed, rare, and Mendelian diseases and serve as resources for pre-clinical studies investigating personalized medicine approaches to their care. The Center uses a variety of genome editing approaches to build mouse models of human disease with the goals of (1) validating new gene-disease relationships, (2) confirming phenotype expansion for known disease genes, and (3) testing new treatment approaches. The Baylor/Rice Genome Editing Testing Center assists researchers with pre-clinical testing of novel genome editing delivery systems and approaches in mouse models. The Center is using novel genome editing reporter mouse models made at Baylor to test the efficacy of new delivery systems and mouse models of human disease to test novel genome editing approaches that may ameliorate or cure disease.
Websites
Selected Publications
- Lanza DG, Mao J, Lorenzo I, Liao L, Seavitt JR, Ljungberg MC, Simpson EM, DeMayo FJ, Heaney JD. "An oocyte-specific Cas9-expressing mouse for germline CRISPR/Cas9-mediated genome editing." Genesis. 2024 Apr;62(2):e23589. Pubmed PMID: 38523431
- Pan X, et al. "De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.." Am J Hum Genet. 2024 Mar 6;S0002-9297(24)00039-9. Pubmed PMID: 38479391
- Ahmed AA, Salas E, Lanza DG, Heaney JD, Pangas SA "Generation of a novel Stra8-driven Cre recombinase strain for use in pre-meiotic germ cells in mice." Biol Reprod. 2023 Aug 10;109(2):184-191. Pubmed PMID: 37279768
- Huang Q, Chen AT, Chan KY, Sorensen H, Barry AJ, Azari B, Zheng Q, Beddow T, Zhao B, Tobey IG, Moncada-Reid C, Eid FE, Walkey CJ, Ljungberg MC, Lagor WR, Heaney JD, Chan YA, Deverman BE "Targeting AAV vectors to the central nervous system by engineering capsid-receptor interactions that enable crossing of the blood-brain barrier." PLoS Biol. 2023 Jul 19;21(7):e3002112. Pubmed PMID: 37467291
- Liang SQ, Walkey CJ, Martinez AE, Su Q, Dickinson ME, Wang D, Lagor WR, Heaney JD, Gao G, Xue W "AAV5 delivery of CRISPR/Cas9 supports effective genome editing in mouse lung airway." Mol Ther. 2022;30(1):238-243. Pubmed PMID: 34695545
- Rana N, Privitera G, Kondolf HC, Bulek K, Lechuga S, De Salvo C, Corridoni D, Antanaviciute A, Maywald RL, Hurtado AM, Zhao J, Huang EH, Li X, Chan ER, Simmons A, Bamias G, Abbott DW, Heaney JD, Ivanov AI, Pizarro TT "GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis." Cell. 2022;185(2):283-298.e17. Pubmed PMID: 35021065
- Webster NJ, Maywald RL, Benton SM, Dawson EP, Murillo OD, LaPlante EL, Milosavljevic A, Lanza DG, Heaney JD "Testicular germ cell tumors arise in the absence of sex-specific differentiation." Development. 2021;148(9):dev197111. Pubmed PMID: 33912935
- Birling MC, et al. "A resource of targeted mutant mouse lines for 5,061 genes." Nat Genet. 2021;53(4):416-419. Pubmed PMID: 33833456
- Lanza DG, Gaspero A, Lorenzo I, Liao L, Zheng P, Wang Y, Deng Y, Cheng C, Zhang C, Seavitt JR, DeMayo FJ, Xu J, Dickinson ME, Beaudet AL, Heaney JD "Comparative analysis of single-stranded DNA donors to generate conditional null mouse alleles." BMC Biol. 2018 Jun 21;16(1):69. Pubmed PMID: 29925370
- Santiago-Sim, Burrage LC, et al. "Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features." Am J Hum Genet. 2017 Apr 6;100(4):676-688. Pubmed PMID: 28343629
Memberships
- International Mammalian Genome Society
- Member
- Genetics Society of America
- Member
- International Society for Transgenic Technology
- Member
- Society for the Study of Reproduction
- Member
Funding
- BCM Knockout Mouse Production and Phenotyping Project - #UM1 HG006348 NIH/NHGRI
- BCM Center for Precision Medicine Models - #U54 OD030165 NIH/OD
- BCM/Rice Genome Editing Testing Center - #U42 OD035581 NIH/OD
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