Project description:We identified region-specific co-expression networks representing distinct molecular pathways in oligodendrocytes associated with human neurological disease. Bioinformatic analyses reveal molecular regulators of these networks and, in this data, we confirmed modulation of network expression in vitro in a human cell line. This work supports identification of targetable region-specific vulnerabilities to neurological disease mediated by oligodendrocytes.
Project description:Through thousands of years of breeding and strong human selection, the dog (Canis lupus familiaris) exists today within hundreds of closed populations throughout the world, each with defined phenotypes. A singular geographic region with broad diversity in dog breeds presents an interesting opportunity to observe potential mechanisms of breed formation. Italy claims 14 internationally recognized dog breeds, with numerous additional local varieties. To determine the relationship among Italian dog populations, we integrated genetic data from 263 dogs representing 23 closed dog populations from Italy, seven Apennine gray wolves. Using 142,840 genome-wide SNPs, this dataset was used in the identification of breed development routes for the Italian breeds that included divergence from common populations for a specific purpose, admixture of regional stock with that from other regions, and isolated selection of local stock with specific attributes.
Project description:Microglia play important roles in developmental and homeostatic brain function, and influence the establishment and progression of many neurological disorders. Here, we demonstrate that renewable human iPSCs can be efficiently differentiated to microglial-like cells (iMGL) to study neurological diseases, such as Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo and whole transcriptome analysis demonstrates that they are highly similar to adult and fetal human microglia. Functional assessment of iMGLs reveal that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. We also show novel use of iMGLs to examine the effects of fibrillar Aβ and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Taken together, these findings demonstrate that iMGLs can be used in high-throughput studies of microglial function, providing important new insight into human neurological disease.
Project description:In this study, beta-TCP was implanted in dog mandibles, after which the gene expression profiles and signaling pathways were monitored using microarray and Ingenuity Pathways Analysis (IPA). Following the extraction of premolars and subsequent bone healing, betaâTCP was implanted into the artificial osseous defect. Total RNA was isolated from bone tissues and gene expression profiles were examined using microarray analysis. We used microarrays to detail the global programme of gene expression and identified distinct classes of up- and down- regulated genes during this process. Waiting 3 months healing after tooth extraction from beagle dog mandibles, we drilled the holes in the dog mandibles, and implanted without and with beta-TCP. And these dog mandibles were selected for RNA extraction and hybridization on Affymetrix microarrays. After implanting beta-TCP in the dog mandibles 4, 7, 14 days, we selected sample at 3 time points: Control_4d, beta-TCP_4d, Control_7d, beta-TCP_7d, Control_14d, beta-TCP_14d.
Project description:Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1-3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. We use genome wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). Two different case-only variants targeted the same approximately 500-bp highly conserved regulatory element between the cadherin genes CDH2 and DSC3. We functionally test these variants in a human neuroblastoma cell line and show that they cause significant changes in gene expression, likely due to disrupted transcription factor binding. This work demonstrates how we can use the unique genetics of dog breeds, and mechanistic similarities between human and dog diseases, to find genes and regulatory pathways underlying complex psychiatric disorders.