Selected Grantee Publications
- Clear All
- 9 results found
- Rare Diseases
- Women's Health
- 2022
Mendelian Gene Identification through Mouse Embryo Viability Screening
Cacheiro et al., Genome Medicine. 2022.
https://www.doi.org/10.1186/s13073-022-01118-7
The investigators dissected phenotypic similarities between patients and model organisms by assessing the embryonic stage at which homozygous loss of function results in lethality in mice of both sexes obtained from the International Mouse Phenotyping Consortium. Information on knockout mouse embryo lethality can be used to prioritize candidate genes associated with certain disorders. Access to unsolved cases from rare-disease genome sequencing programs allows for the screening of those genes for potentially pathogenic variants, which could lead to a diagnosis and new potential treatment options to inform the management of human disease. Supported by ORIP (UM1OD023221, UM1OD023222, U42OD011174) and NHGRI.
Maternal Western-Style Diet Reduces Social Engagement and Increases Idiosyncratic Behavior in Japanese Macaque Offspring
Mitchell et al., Brain, Behavior, and Immunity. 2022.
https://www.doi.org/10.1016/j.bbi.2022.07.004
Evidence points to an association between maternal obesity and risk of early-emerging neurodevelopmental disorders in offspring, yet few preclinical studies have tested for associations between maternal Western-style diet (mWSD) and offspring behavior. Using Japanese macaques, researchers found that mWSD offspring exhibited less proximity to peers and initiated fewer affiliative social behaviors. These outcomes appear to be mediated by increased maternal interleukin-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin. These findings suggest specific prevention and intervention targets for early-emerging neurodevelopmental disorder in humans. Supported by ORIP (P51OD011092), NIMH, and NICHD.
De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila
Chung et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac053
Variants in EMC1, which encodes a subunit of the endoplasmic reticulum (ER)–membrane protein complex (EMC), are associated with developmental delay in children. Functional consequences of these variants are poorly understood. The investigators identified de novo variants in EMC1 in three children affected by global developmental delay, hypotonia, seizures, visual impairment, and cerebellar atrophy. They demonstrated in Drosophila that these variants are loss-of-function alleles and lead to lethality when expressed in glia but not in neurons. This work suggests the causality of EMC variants in disease. Supported by ORIP (R24OD022005, R24OD031447), NINDS, and NICHD.
X Chromosome Agents of Sexual Differentiation
Arnold et al., Nature Reviews Endocrinology. 2022.
https://www.doi.org/10.1038/s41574-022-00697-0
Many diseases affect one sex disproportionately. A major goal of biomedical research is to understand which sex-biasing factors influence disease severity and to develop therapeutic strategies to target these factors. Two groups of such agents are sex chromosome genes and gonadal hormones. Researchers use the “four core genotypes” model to enable comparisons among animals with different sex chromosomes but the same type of sex hormones, which allows investigators to distinguish disease mechanisms influenced by the sex chromosomes. Supported by ORIP (R01OD030496, R21OD026560), NICHD, NIDDK, and NHLBI.
Stromal P53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner
Wu et al., Molecular Cancer Research. 2022.
https://www.doi.org/10.1158/1541-7786.MCR-21-0960
Loss of stromal p53 function drives tumor progression in breast cancer, but the exact mechanisms have been relatively unexplored. Using mouse models, researchers demonstrated that loss of cancer-associated fibroblast (CAF) p53 enhances carcinoma formation driven by oncogenic KRAS G12D, but not ERBB2, in mammary epithelia. These results corresponded with increased tumor cell proliferation and DNA damage, as well as decreased apoptosis, in the KRAS G12D model. Furthermore, a gene cluster associated with CAF p53 deficiency was found to associate negatively with survival in microarray and heat map analyses. These data indicate that stromal p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately affects patient survival. Supported by ORIP (K01OD026527) and NCI.
Sunitinib Inhibits STAT3 Phosphorylation in Cardiac Muscle and Prevents Cardiomyopathy in the mdx Mouse Model of Duchenne Muscular Dystrophy
Oliveira-Santos et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac042
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, affecting about 1 in 5,000 boys worldwide. DMD is a fatal X-linked genetic disorder that results from mutations in the dystrophin gene and leads to progressive muscular degeneration. Individuals with DMD often die at a young age from respiratory or heart failure. To date, few studies have examined the basis of cardiac failure associated with DMD, and no effective U.S. Food and Drug Administration (FDA)–approved treatment options are available. Using a mouse model of both sexes, researchers characterized the effectiveness of sunitinib, an FDA-approved small-molecule drug, in preventing DMD-related cardiomyopathy. The treatment reduced STAT3 activation in cardiac muscle and prevented cardiomyopathy disease progression. Inhibition of STAT3 activation in cardiac muscle can reduce inflammation and fibrosis and prevent heart failure. These findings demonstrate sunitinib’s potential as a novel treatment option for skeletal and cardiac muscle dysfunction in patients with DMD. Supported by ORIP (R42OD030543).
A Novel DPH5-Related Diphthamide-Deficiency Syndrome Causing Embryonic Lethality or Profound Neurodevelopmental Disorder
Shankar et al., Genetics in Medicine. 2022.
https://www.doi.org/10.1016/j.gim.2022.03.014
Neurodevelopmental disorders (NDDs) affect more than 3% of the pediatric population and often have associated neurologic or multisystem involvement. The underlying genetic etiology of NDDs remains unknown in many individuals. Investigators characterized the molecular basis of NDDs in children of both sexes with nonverbal NDDs from three unrelated families with distinct overlapping craniofacial features. The investigators also used a mouse model of both sexes to determine the pathogenicity of variants of uncertain significance, as well as genes of uncertain significance, to advance translational genomics and provide precision health care. They identified several variants in DPH5 as a potential cause of profound NDD. Their findings provide strong clinical, biochemical, and functional evidence for DPH5 variants as a novel cause of embryonic lethality or profound NDD with multisystem involvement. Based on these findings, the authors propose that “DPH5-related diphthamide deficiency syndrome” is a novel autosomal-recessive Mendelian disorder. Supported by ORIP (K01OD026608, U42OD012210) and NHGRI.
Common and Divergent Features of T Cells From Blood, Gut, and Genital Tract of Antiretroviral Therapy–Treated HIV+ Women
Xie et al., Journal of Immunology. 2022.
https://www.doi.org/10.4049/jimmunol.2101102
T cells residing in mucosal tissues play important roles in homeostasis and defense against microbial pathogens, but how organ system environments affect the properties of resident T cells is relatively unknown. Researchers phenotyped T cells in the gut and reproductive tract using blood and tissue samples from women with HIV who have achieved viral suppression via antiretroviral therapy. The T cells exhibited differing expression of CD69 and CD103 markers, whereas resident memory CD8+ T cells from the female reproductive tract expressed PD1 preferentially. Additionally, CXCR4+ T inflammatory mucosal cells expressed multiple chemokine receptors differentially. These results suggest that T cells take on distinct properties in different mucosal sites, which allows them to tailor activities to their surrounding milieu. This study offers important insights for reproductive medicine in women. Supported by ORIP (S10OD018040), NHLBI, NIAID, and NIDDK.
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Zhang et al., Cancer Research. 2022.
https://pubmed.ncbi.nlm.nih.gov/34965933/
Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T cell viral immunity against tumor cells. Investigators developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Based on functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus in ovarian cancer patients, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. The streamlined and systemic approach includes assessing APEC function in vivo using a new zebrafish xenograft platform that facilitates high-resolution single-cell imaging to assess therapy responses and then validating top candidates using traditional mouse xenograft studies and primary patient samples. This study develops a high-throughput preclinical platform to identify patient-specific antibody-peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma. Supported by ORIP (R24OD016761).