Biology subjects

Virtanen, C.

Publications and source records attributed to Virtanen, C..

3 recordsLinked to original sources

bioRxiv2024

Translational profiling reveals novel gene expression changes in the direct and indirect pathways in a mouse model of LDOPA-induced dyskinesia

The molecular mechanisms underlying L-dihydroxyphenylalanine (LDOPA) induced dyskinesia in Parkinsons disease are poorly understood. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively isolate RNA from either DRD1A expressing striatonigral, or DRD2 expressing striatopallidal medium spiny neurons (MSNs) of the direct and indirect pathways respectively, to study changes in translational gene expression following repeated LDOPA treatment. 6-OHDA lesioned DRD1A and DRD2 BacTRAP mice were treated with either saline or LDOPA bi-daily for 21 days over which time they developed abnormal involuntary movements reminiscent of dyskinesia. On day 22, all animals received LDOPA 40 minutes prior to sacrifice. The striatum of the lesioned hemisphere was dissected and subject to TRAP. Extracted ribosomal RNA was amplified, purified and gene expression was quantified using microarray. 195 significantly varying transcripts were identified among the 4 treatment groups. Pathway analysis revealed an overrepresentation of calcium signaling and long-term potentiation in the DRD1A expressing MSNs of the direct pathway, with significant involvement of long-term depression in the DRD2 expressing MSNs of the indirect pathway following chronic treatment with LDOPA. Several MAPK associated genes (NR4A1, GADD45G, STMN1, FOS and DUSP1) differentiated the direct and indirect pathways following both acute and chronic LDOPA treatment. However, the MAPK pathway activator PAK1 was downregulated in the indirect pathway and upregulated in the direct pathway, strongly suggesting a role for PAK1 in regulating the opposing effects of LDOPA on these two pathways in dyskinesia. Future studies will assess the potential of targeting these genes and pathways to prevent the development of LDOPA-induced dyskinesia.

neuroscience↗

bioRxiv2021

CanDIG: Secure Federated Genomic Queries and Analyses Across Jurisdictions

Rapid expansions of bioinformatics and computational biology have broadened the collection and use of -omics data including genomic, transcriptomic, methylomic and a myriad of other health data types, in the clinic and the laboratory. Both clinical and research uses of such data require co-analysis with large datasets, for which participant privacy and the need for data custodian controls must remain paramount. This is particularly challenging in multi-jurisdictional settings, such as Canada, where health privacy and security requirements are often heterogeneous. Data federation presents a solution to this, allowing for integration and analysis of large datasets from various sites while abiding by local policies. The Canadian Distributed Infrastructure for Genomics platform (CanDIG) enables federated querying and analysis of -omics and health data while keeping that data local and under local control. It builds upon existing infrastructures to connect five health and research institutions across Canada, relies heavily on standards and tooling brought together by the Global Alliance for Genomics and Health (GA4GH), implements a clear division of responsibilities among its participants and adheres to international data sharing standards. Participating researchers and clinicians can therefore contribute to and quickly access a critical mass of -omics data across a national network in a manner that takes into account the multi-jurisdictional nature of our privacy and security policies. Through this, CanDIG gives medical and research communities the tools needed to use and analyze the ever-growing amount of -omics data available to them in order to improve our understanding and treatment of various conditions and diseases. CanDIG is being used to make genomic and phenotypic data available for querying across Canada as part of data sharing for five leading pan-Canadian projects including the Terry Fox Comprehensive Cancer Care Centre Consortium Network (TF4CN) and Terry Fox PRecision Oncology For Young peopLE (PROFYLE), and making data from provincial projects such as POG (Personalized Onco- Genomics) more widely available.

genomics↗

bioRxiv2017

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

cancer biology↗