Katie is interested in translational genomics using animals as models for human diseases, with an emphasis on neurodegenerative diseases and early detection.
Doctor of Philosophy, University of California Davis (2018)
Master of Science, University of Nebraska - Lincoln, Animal Breeding and Genetics (2014)
Bachelor of Science, Calif State Polytechnic University (2012)
Thomas Montine, Postdoctoral Faculty Sponsor
Community and International Work
Stanford Brain Day
Opportunities for Student Involvement
Letters to a Pre-Scientist
Opportunities for Student Involvement
Skype a Scientist
Opportunities for Student Involvement
TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290500179
Visualizing innate immune activation in a mouse model of Parkinson's disease using a highly specific TREM1-PET tracer.
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290500016
- Monocyte lineage-specific glucocerebrosidase expression in human hematopoietic stem cells: A universal genome editing strategy for Gaucher disease ACADEMIC PRESS INC ELSEVIER SCIENCE. 2020: S64–S65
Development of a CD19 PET tracer for detecting B cells in a mouse model of multiple sclerosis.
Journal of neuroinflammation
2020; 17 (1): 275
B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE).Female C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1-125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted.Radiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/μmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry-providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice.CD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.
View details for DOI 10.1186/s12974-020-01880-8
View details for PubMedID 32948198
- Author Correction: Engineering monocyte/macrophage-specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing. Nature communications 2020; 11 (1): 4231
Engineering monocyte/macrophage−specific glucocerebrosidase expression in human hematopoietic stem cells using genome editing
2020; 11: 1-14
View details for DOI 10.1038/s41467-020-17148-x
Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds
2018; 14 (12): e1007850
Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds.
View details for DOI 10.1371/journal.pgen.1007850
View details for Web of Science ID 000455099000032
View details for PubMedID 30521570
View details for PubMedCentralID PMC6303079
A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs
G3-GENES GENOMES GENETICS
2018; 8 (8): 2773–80
Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of young adult Rottweiler dogs (Canis lupus familiaris) characterized pathologically by axonal spheroids primarily targeting sensory axon terminals. A genome-wide association study of seven Rottweilers affected with NAD and 42 controls revealed a significantly associated region on canine chromosome 5 (CFA 5). Homozygosity within the associated region narrowed the critical interval to a 4.46 Mb haplotype (CFA5:11.28 Mb - 15.75 Mb; CanFam3.1) that associated with the phenotype. Whole-genome sequencing of two histopathologically confirmed canine NAD cases and 98 dogs unaffected with NAD revealed a homozygous missense mutation within the Vacuolar Protein Sorting 11 (VPS11) gene (g.14777774T > C; p.H835R) that was associated with the phenotype. These findings present the opportunity for an antemortem test for confirming NAD in Rottweilers where the allele frequency was estimated at 2.3%. VPS11 mutations have been associated with a degenerative leukoencephalopathy in humans, and VSP11 should additionally be included as a candidate gene for unexplained cases of human NAD.
View details for DOI 10.1534/g3.118.200376
View details for Web of Science ID 000440327400022
View details for PubMedID 29945969
View details for PubMedCentralID PMC6071611
Canine NAPEPLD-associated models of human myelin disorders
2018; 8: 5818
Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs. Genome-wide association study (GWAS) allowed us to map LEMP in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene, encoding an enzyme of the endocannabinoid system. We then sequenced this gene in LEMP-affected Rottweilers and identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.
View details for DOI 10.1038/s41598-018-23938-7
View details for Web of Science ID 000429684000027
View details for PubMedID 29643404
View details for PubMedCentralID PMC5895582
Evaluation of reduced subsets of single nucleotide polymorphisms for the prediction of age at puberty in sows
2015; 46 (4): 403–9
Genomic information could be used efficiently to improve traits that are expensive to measure, sex limited or expressed late in life. This study analyzed the phenotypic variation explained by major SNPs and windows for age at puberty in gilts, an indicator of reproductive longevity. A genome-wide association study using 56, 424 SNPs explained 25.2% of the phenotypic variation in age at puberty in a training set (n = 820). All SNPs from the top 10% of 1-Mb windows explained 33.5% of the phenotypic variance compared to 47.1% explained by the most informative markers (n = 261). In an evaluation population, consisting of subsequent batches (n = 412), the predictive ability of all SNPs from the major 1-Mb windows was higher compared to the variance captured by the most informative SNP from each of these windows. The phenotypic variance explained in the evaluation population varied from 12.3% to 36.8% when all SNPs from major windows were used compared to 6.5-23.7% explained by most informative SNPs. The correlation between phenotype and genomic prediction values based on SNP effects estimated in the training population was marginal compared to their effects retrained in the evaluation population for all (0.46-0.81) or most informative SNPs (0.30-0.65) from major windows. An increase in genetic gain of 20.5% could be obtained if genomic selection included both sexes compared to females alone. The pleiotropic role of major genes such as AVPR1A could be exploited in selection of both age at puberty and reproductive longevity.
View details for DOI 10.1111/age.12310
View details for Web of Science ID 000358641800008
View details for PubMedID 26059234
Genome-wide analysis of TNF-alpha response in pigs challenged with porcine circovirus 2b
2015; 46 (2): 205–8
Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine with a role in activating adaptive immunity to viral infections. By inhibiting the capacity of plasmacytoid dendritic cells to produce interferon-α and TNF-α, porcine circovirus 2 (PCV2) limits the maturation of myeloid dendritic cells and impairs their ability to recognize viral and bacterial antigens. Previously, we reported QTL for viremia and immune response in PCV2-infected pigs. In this study, we analyzed phenotypic and genetic relationships between TNF-α protein levels, a potential indicator of predisposition to PCV2 co-infection, and PCV2 susceptibility. Following experimental challenge with PCV2b, TNF-α reached the peak at 21 days post-infection (dpi), at which time a difference was observed between pigs that expressed extreme variation in viremia and growth (P < 0.10). A genome-wide association study (n = 297) revealed that genotypes of 56,433 SNPs explained 73.9% of the variation in TNF-α at 21 dpi. Major SNPs were identified on SSC8, SSC10 and SSC14. Haplotypes based on SNPs from a SSC8 (9 Mb) 1-Mb window were associated with variation in TNF-α (P < 0.02), IgG (P = 0.05) and IgM (P < 0.13) levels at 21 dpi. Potential overlap of regulatory mechanisms was supported by the correlations between genomic prediction values of TNF-α and PCV2 antibodies (21 dpi, r > 0.22), viremia (14-21 dpi, P > 0.29) and viral load (r = 0.31, P < 0.0001). Characterization of the QTL regions uncovered genes that could influence variation in TNF-α levels as well as T- and B-cell development, which can affect disease susceptibility.
View details for DOI 10.1111/age.12262
View details for Web of Science ID 000351410200013
View details for PubMedID 25643812