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| ===== Research Overview ===== | ===== Research Overview ===== |
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| Development and function of multicellular organisms requires coordinated actions of many genes that interact with each other and are expressed in dynamic patterns. Alterations in gene networks can cause many abnormalities including cancers and neuronal degeneration. Hence, understanding genetic interactions and spatiotemporal regulation of gene expression are critical to gaining important insights into the pathogenesis of human diseases.\\ | How cells form tissues? How do they communicate with each other and respond to environmental signals? How cell-cell interactions give rise to complex animal behavior? How external and internal signals control stress response and aging in animals? Finding answers to these major questions requires identification of key genes and understanding their expression and functional crosstalk. Since many such genes are also linked to diseases such as cancers, neuronal degeneration and premature death, a detailed knowledge of the regulatory networks of gene interactions and function will ultimately help develop treatments for major illnesses thereby improving human health and lifespan.\\ |
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| Toward this goal we are investigating three conserved biological processes, namely, cell signaling, cell proliferation and differentiation, in two well-established model organisms (nematodes or worms), //C. elegans// and //C. briggsae//. These two species offer many experimental advantages including rapid development (~3 days from egg to adult), transparency, small (~1 mm), hermaphroditic life style, and compact genome (~100 megabases). Approximately two-thirds of the genes in worms have human homologs and many of the gene function and cellular and molecular processes are conserved all the way to human.\\ | My group is investigating fundamental biological processes, e.g., cell signaling, cell proliferation, cell differentiation, and regulation of stress response, in two well-established animal models, //C. elegans// and //C. briggsae//. These two nematode species (or worms) offer many experimental advantages including rapid development (~3 days from egg to adult), transparency, small size (~1 mm), hermaphroditic life style, and compact genome (~100 megabases). Approximately two-thirds of the genes in worms have human homologs and many of the gene function and cellular and molecular processes are conserved all the way to human.\\ |
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| Specific research topics in our lab include:\\ | Major areas of research in our lab focus on:\\ |
| * Signaling pathway function and crosstalks | * Signaling pathways and networks |
| * Tissue morphogenesis | * Developmental genetics |
| * Transcriptional regulation | * //C. briggsae// genetics (read [[http://www.briggsae.org|here]]) |
| * Cancer genetics | * Regulation of stress response and aging |
| * //C. briggsae// linkage maps (read [[http://www.briggsae.org/|here]]) | |
| * Functional genomics in //Caenorhabditis// nematodes | |
| * Neurobiology and drug discovery (read more about it [[http://www.macwormlab.net/labchip/|here]]) | |
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| | Read about our past work on electrotaxis ([[http://www.macwormlab.net/labchip/|here]]). We are continuing to use the assay to investigate stress response and neuronal aging. Check out our papers in the [[pubs|publication]] section. |
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| ==== LIM-HOX gene lin-11 ==== | One of the genes that we have investigated for their role in reproductive system development is a LIM homeobox transcription factor LIN-11. Our findings have established that LIN-11 is a key regulator of vulval morphogenesis. In //lin-11// mutant animals, vulval cells fail to acquire correct identities and inappropriately fuse with each other (Gupta et.al, 2003). Thus, //lin-11// confers cell identity by regulating the expression of cell type-specific genes. We are taking a variety of approaches in Genetics, Molecular Biology and Bioinformatics to understand the molecular basis of //lin-11// regulation and its downstream targets during vulval morphogenesis (e.g., see [[https://pubmed.ncbi.nlm.nih.gov/28215941/|Amon & Gupta, 2017]]).\\ |
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| One of the projects involves investigating the regulation and function of a LIM homeobox transcription factor LIN-11. LIN-11 is a key regulator of vulval morphogenesis. In //lin-11// mutant animals, vulval cells fail to acquire correct identities and inappropriately fuse with each other (Gupta et.al, 2003). Thus, //lin-11// confers cell identity by regulating the expression of cell type-specific genes. We are taking a variety of approaches in Genetics, Molecular Biology and Bioinformatics to understand the molecular basis of //lin-11// regulation and its downstream targets during vulval morphogenesis.\\ | |
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| ==== Wnt Signalling ==== | More recently, we have collaborated with Dr. Chamberlin (Ohio State University, USA) to discover a new class of genes that inhibit cell proliferation (termed 'inappropriate vulva proliferation' or //ivp//). Our work ([[https://pubmed.ncbi.nlm.nih.gov/31960924/|Chamberlin et al. 2019]]) has revealed that //ivp// genes encode novel, nuclear proteins that are important for chromatin-mediated gene regulation. |
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| Another project deals with the regulation of Wnt Signal transduction pathway. Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in //Drosophila// and //C. elegans//; biochemistry in cell culture and ectopic gene expression in Xenopus embryos. Mutations in Wnt genes or Wnt pathway components lead to specific developmental defects, while various human diseases, including cancer, are caused by abnormal Wnt signaling. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to beta-catenin, which enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.\\ | |
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| | ===== Stress response and aging ===== |
| | Another major focus of our lab is to investigate the mechanism of stress response and how it affects the behaviour and aging of animals. |
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| | We have shown that an Axin family member in //C. elegans//, termed //pry-1//, plays an essential role in the maintenance of stress response and normal lifespan of animals. Axins are bona-fide components of Wnt signal transduction pathway ([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956378/|see this review]]). Mutations in Wnt signaling components lead to a variety of defects. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through Axin and several other cytoplasmic relay components, the signal is transduced to beta-Catenin, which enters the nucleus and interacts with TCF to regulate gene expression changes.\\ |
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| | Interestingly, our work has suggested that PRY-1's role in aging does not involve any of the known factors of Wnt signaling. The data demonstrate that PRY-1 interacts with AAK-2 (AMP Kinase) and DAF-16 (FOXO family member), presumably in the form of a complex, to regulate genes involved in lifespan maintenance [[https://www.biorxiv.org/content/10.1101/2020.04.22.055962v1.full|read the paper]].\\ |
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| | In addition to PRY-1, our lab has been investigating a neurotrophic factor, MANF (Mesencephalic astrocyte-derived neurotrophic factor) in //C. elegans// stress response maintenance and neuroprotection. We provided the first evidence of MANF-1's role in ER-stress maintenance and dopaminergic neuroprotection. [[https://www.frontiersin.org/articles/10.3389/fnins.2018.00544/full|Richman et al. 2018]]. |
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| ===== Electrotaxis ===== | ===== Electrotaxis ===== |
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| {{ :images:electrotaxis.gif?400|}}Our lab is also investigating the electrotaxis sensory behavior in nematodes. In collaboration with Ravi Selvaganapathy (Mechanical Engineering, McMaster University) <color blue>we provided the first evidence of electrotaxis response in //C. elegans// in a microfluidic channel environment (Rezai et al., Lab Chip 2010). We showed that a DC electric field stimulus induces the worm to swim towards cathode with a characteristic speed that is robust, instantaneous and highly sensitive.</color> Subsequently, we demonstrated that dopamine (DA) neurons play important role in mediating the electrotaxis behavior. The involvement of DA signalling has allowed us to model Parkinson's disease in //C. elegans//, in order to understand the mechanism of neurodegeneration and to identify neuorprotective chemicals. | {{ :images:electrotaxis.gif?400|}}Our lab is also investigating the mechanism of electrotaxis behaviour in nematodes and its applications.\\ |
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| | **Electrotaxis is the movement of the organism in response to an electric field stimulus.** In collaboration with Ravi Selvaganapathy (Mechanical Engineering, McMaster University) <color blue>we provided the first evidence of electrotaxis response of //C. elegans// in a microfluidic device (Rezai et al., Lab Chip 2010). We demonstrated that worms, when exposed to a low voltage DC current inside a liquid-filled micro-channel, move in a directed manner towards cathode with a characteristic speed. This response is robust, instantaneous, and highly sensitive.</color> Subsequently, we demonstrated that dopamine (DA) neurons play an important role in mediating the behavior. The involvement of DA signalling provides a basis to model Parkinson's disease in //C. elegans//, and to investigate the mechanism of neurodegeneration as well as to screen for chemicals with neuorprotective properties. |