A5001329171- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Neurological diseases and metabolism
- Immunodeficiency and Autoimmune Disorders
- Glycosylation and Glycoproteins Research
- Lysosomal Storage Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Neurogenetic and Muscular Disorders Research
- Neurological disorders and treatments
- IL-33, ST2, and ILC Pathways
- Congenital heart defects research
- Amyotrophic Lateral Sclerosis Research
- Blood disorders and treatments
- Ocular Diseases and Behçet’s Syndrome
- Genetics and Neurodevelopmental Disorders
- Genetic Neurodegenerative Diseases
- Autophagy in Disease and Therapy
- Neonatal Respiratory Health Research
- Galectins and Cancer Biology
- Cardiovascular Conditions and Treatments
- Cardiomyopathy and Myosin Studies
- Genomics and Phylogenetic Studies
- Genetics, Aging, and Longevity in Model Organisms
- FOXO transcription factor regulation
- Endoplasmic Reticulum Stress and Disease
Missouri College
2016-2024
University of Missouri
2014-2024
Washington University in St. Louis
2021-2024
Center for Rheumatology
2022
Mayo Clinic in Florida
2021-2022
Background Previous reports associated 2 mutant SOD 1 alleles ( 1:c.118A and 1:c.52T ) with degenerative myelopathy in 6 canine breeds. The distribution of these other breeds has not been reported. Objective To describe the 222 Animals DNA from 33,747 dogs was genotyped at 1:c.118 , 1:c.52 or both. Spinal cord sections 249 were examined. Methods Retrospective analysis 35,359 previously determined genotypes 1:c.118G>A 1:c.52A>T prospective survey to update clinical status a subset which...
Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific dysregulation, we used a mouse model carrying missense variant (p.G421R) that causes human disease. We observed spontaneous imiquimod (IMQ)-induced skin inflammation cell-intrinsic local Th17 responses GOF mice. CD4+ T cells were sufficient to drive showed increased Il22 expression expanded clones. Certain aspects...
Natural Killer (NK) cells are innate immune lymphocytes important for host viral and tumor immunity. We investigated the requirement ATP citrate lyase (ACLY) in NK cell function using an inducible genetic mouse model. ACLY regulates citrate-malate shuttle, generating cytosolic acetyl-coenzyme A that is primarily used acetylation or lipid synthesis. ACLY-deficient had significant defects upon activation via IL-15 priming including impaired glycolysis, proliferation, cytokine production,...
We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months age. As the progressed these included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment localized generalized seizures. A whole genome sequence, generated DNA from one affected dog, contained plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce frameshift premature termination codon...
Significance Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM promising model for ALS, because genome-wide association identified mutation superoxide dismutase 1 gene ( SOD1 ), known ALS gene. This found many dog breeds increases the risk of DM, and pathological findings clinical progression two diseases are similar. In this study, we identify modifier gene, SP110 nuclear body protein ) , which...
Primary immune regulatory disorders (PIRD) represent a group of characterized by dysregulation, presenting with wide range clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result PIRD broad spectrum. Studies patients have documented decreased frequency FOXP3+ Tregs and an increased Th17 cells some active disease. However, the mechanisms disease pathogenesis GOF syndrome remain largely...
Neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative disease, has been diagnosed in young adult Australian Cattle Dogs.Characterize the Dog form of NCL and determine its molecular genetic cause.Tissues from 4 Dogs with NCL-like signs buccal swabs both parents fifth affected breed member. Archived DNA samples 712 individual dogs were genotyped.Tissues examined by fluorescence, electron, immunohistochemical microscopy. A whole-genome sequence was generated for 1 dog. TaqMan allelic...
Loss of either PINK1 or PRKN causes an early onset Parkinson’s disease (PD) phenotype. Functionally, and work together to mediate stress-activated mitochondrial quality control. Upon damage, PINK1, a ubiquitin kinase PRKN, ligase, decorate damaged organelles with phosphorylated for sequestration degradation in lysosomes, process known as mitophagy. While several genetic mutations are established result loss mitophagy function, many others have not been extensively characterized unknown...
Abstract Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility MAC infections in canine breed. Adult Miniature Schnauzers developing progressive systemic were related common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study homozygosity mapping using 8 infected, 9 non-infected relatives, 160 control detected...
A 10‐month‐old spayed female Cane Corso dog was evaluated after a 2‐month history of progressive blindness, ataxia, and lethargy. Neurologic examination abnormalities indicated multifocal lesion with primarily cerebral cerebellar signs. Clinical worsening resulted in humane euthanasia. On necropsy, there marked astrogliosis throughout white matter tracts the cerebrum, most prominently corpus callosum. In cortex midbrain, neurons contained large amounts autofluorescent storage material...
Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records videos episodes from 25 affected dogs were reviewed. hyperkinesia dystonia lasted several minutes to hours could occur often >10/day. They not associated with strenuous exercise or fasting but sometimes triggered...
NK effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. cell production IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine cells exhibit metabolic requirements for production, which are reversed receptor-mediated stimulation following IL-15 priming. Although both cytokine receptor leads to similar protein only upregulates Ifng transcript, suggesting that is translationally regulated...
Consistent with a tentative diagnosis of neuronal ceroid lipofuscinosis ( NCL ), autofluorescent cytoplasmic storage bodies were found in neurons from the brains 2 related Shiba Inu dogs young‐adult onset, progressive neurodegenerative disease. Unexpectedly, no potentially causal ‐related variants identified whole‐genome sequence generated DNA 1 affected dogs. Instead, contained homozygous 3 base pair (bp) deletion coding region HEXB . The other dog also was for this 3‐bp deletion. Mutations...
The implementation of severe combined immunodeficiency (SCID) newborn screening has played a pivotal role in identifying these patients early life as well detecting various milder forms T cell lymphopenia (TCL). In this study we reviewed the diagnostic and clinical outcomes, interesting immunology findings term infants referred to tertiary care center with abnormal SCID screens over 6-year period. Key included 33% incidence non-SCID TCL including novel variants FOXN1, TBX1, MYSM1, POLD1,...
Natural killer (NK) effector functions can be triggered by inflammatory cytokines and engagement of activating receptors. NK cell production IFN-γ, an important immunoregulatory cytokine, exhibits activation-specific IFN-γ regulation. Resting murine cells exhibit metabolic requirements for production, which are reversed receptor-mediated stimulation following IL-15 priming. While both cytokine receptor leads to similar protein only upregulates Ifng transcript, suggesting that is...
Abstract Natural Killer (NK) cells, crucial for viral immunity and tumor clearance, are influenced by metabolism. A prior study revealed that cytokine stimulation boosts the citrate-malate shuttle cytosolic acetyl-CoA through ATP citrate lyase (ACLY) in NK cells. Acetyl-CoA is vital fatty acid synthesis protein acetylation, including histones. To explore role of ACLY cell function, we generated an inducible NK-specific Acly knockout mouse model. loss NKp46+ cells did not alter maturation or...
Abstract A number of efforts are underway to better understand the role genetic variation in successful aging and longevity. However, date, only two genes have been consistently associated with longevity humans: APOE FOXO3, ɛ2 allele also protective against dementia. Recently, using an exome-wide SNP array approach, a missense variant CLEC3B c.316G>A (rs13963 p.S106G) was reported associate independent cohorts Japanese Chinese participants. Interestingly, p.S106G is more frequent...