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  • 2018-2022
  • Wellcome Trust
  • WT|Cell and Developmental Biology
  • OA Publications Mandate: Yes
  • 2019

  • Funder: WT Project Code: 212246
    Funder Contribution: 990,352 GBP

    Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway. Plasma membrane proteins destined for degradation are internalised, enter the endosome, and then transit to the lysosome. Many crucial proteins follow this pathway, with epidermal growth factor receptor (EGFR) an exemplar because of its biological and biomedical importance. EGFR transport to the lysosome requires a crucial event; the receptor is ubiquitinated and then enters membrane vesicles that bud into the lumen of the endosome, to form the multivesicular body. The molecular machinery that drives multivesicular body formation must overcome a complex topological problem: it recognises ubiquitinated EGFR on the cytoplasmic face of the endosome, generates vesicles that capture EGFR inside the endosome, but escapes itself. How this works remains mysterious, but we aim to solve it. We will reassemble the machinery from its component parts on artificial endosomes, and dissect biochemically how it envelops EGFR. We will also examine how the machinery is activated by EGFR, ensuring EGFR’s efficient capture.

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  • Funder: WT Project Code: 219994

    The neuromesodermal progenitors (NMPs) are a group of cells found in the developing embryo, which form the spinal cord and surrounding muscle. NMPs are present at the tail end of the embryo, first producing the head, then trunk and finally the tail end, changing the genes they express as they do this. A subset of these time-regulated genes includes the HOX genes, named HOX1-HOX13. At early stages, NMPs poised to make the neck express HOX1, while successively later NMPs that make the trunk and tail progressively express more of the genes until HOX13 is expressed in tail tip. Studies removing these genes showed that each one is necessary to make vertebrae of a particular identity. It is unknown whether the expression of HOX genes in NMPs at different times during development is important to set identity. It is currently only possible to make NMPs in culture with neck and upper trunk identity. Therefore, I hope to develop a method to make human NMPs which express all the Hox codes. Once we have done this, we will research what is controlling how the cells gain Hox identity. Finally, I will research if HOX code controls NMP differentiation when placed into embryos.

    more_vert
  • Funder: WT Project Code: 220025

    The transcription of almost all genes occurs via random transitions between active and inactive gene states. The net mRNA production is determined by the frequency and size of the resulting random bursts of mRNA synthesis, making gene expression a stochastic process. As a consequence, responses of individual immune cells upon bacterial infection are highly variable, resulting in different infection outcomes. For example, only a subset of innate immune macrophages may accurately recognize and kill invading bacteria. In this project, using mathematical modelling of transcriptional bursting, inference of single-cell genomics and live-cell imaging data, I aim to understand mechanisms involved in coordination of the innate immune responses to pathogen stimulation. In particular, I will study how the foodborne Listeria monocytogenes manipulates the host cell’s gene expression and signalling responses in order to establish a successful infection. I hypothesise that modulation of transcriptional bursting characteristics is a key control mechanism that allows the host to fine-tune its response to pathogen infection, and in turn enables the pathogen to implement its infection strategy. Mechanistic understanding of transcriptional dynamics induced by bacterial infection will inform strategies to improve infection outcomes in the future.

    more_vert
  • Funder: WT Project Code: 220093

    Haematopoietic stem cells (HSCs) have been used for the treatment of diseases including immune deficiencies and metabolic disorders, as well as bone marrow repair after radiation treatment. In order to harvest their full potential, it is essential that we expand our understanding of HSC development and function. A vital part of HSC generation in the developing embryo is the transition of a subset of endothelial cells into blood cells. This occurs under the control of a multitude of factors within the cell and those present in the surrounding environment, the hematopoietic niche. The cell cycle has been shown to be an important involved in the cellular differentiation process, as some cells need to exit the cell cycle in order to undergo the transcriptional and morphological changes associated with differentiation. In my project I will investigate the impact of various factors as cell cycle regulators in this early differentiation of endothelial cells into haematopoietic cells. These studies will employ genetically modified mice, alongside state-of-the-art in-vitro and transcriptional profiling techniques such as single-cell RNA-sequencing. We expect our research to help elucidate the origin of HSCs and therefore contribute to our understanding of how to generate these cells in-vitro.

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  • Funder: WT Project Code: 220005

    High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The 5-year survival rate is low, as patients are often diagnosed after cancer cells have spread from the ovary to other parts of the body. Their preferred site to spread to is the omentum, which is the fatty tissue covering the abdomen. The omentum provides an environment, named the metastatic niche, that supports cancer cell migration, growth and survival, enabling a tumour to form. Fibroblasts are a type of cell within the omentum which are partly responsible for forming this environment. They do so through the assembly of a protein fibre meshwork which surrounds the cancer cells, named the extracellular matrix (ECM). However, how fibroblasts in the omentum become able to assemble ECM in a manner which allows cancer cells to thrive is not yet understood. During my PhD project, I aim to develop a better understanding of how fibroblasts assemble ECM in this way to create a suitable environment for tumour formation within the omentum. To achieve this, I plan to use techniques including CRISPR, fluorescence microscopy and BioID in cell lines I will generate from ovarian cancer patient omentum samples.

    more_vert
  • Funder: WT Project Code: 220572

    Background Oxidised LDL (oxLDL) forms a significant component of fatty plaques, or atherosclerotic lesions, that accumulate in coronary artery disease and can cause heart attacks or strokes. We have recently developed an antibody to oxLDL, LO1,that can target atherosclerotic plaques. Approach I aim to harness LO1 and other antibody fragments for targeting of nanoparticles to atherosclerotic plaque. I will develop nanoparticles that are capable of carrying a drug, that will be released when it reaches its destination (i.e. the atherosclerotic plaque). I will produce varying designs with different drugs and targeting agents and aim to demonstrate effective delivery of the nanoparticles. I will test these nanoparticles in mouse models of atherosclerosis, as well as a newly developed original experimental model using an amputated human limb. I will then fill the nanoparticles with the drug and aim to demonstrate a beneficial effect. Expected Impact The novel nanoparticles targeted to atherosclerotic plaque will provide a means of local delivery of drugs directly to diseased areas. This will permit much smaller drug doses to be used, with therefore fewer unwanted side effects. In addition, the drugs can be tailored to an individual, utilising the most suitable drug to treat each patient’s atherosclerotic plaques.

    visibility23
    visibilityviews23
    downloaddownloads18
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 220088

    Lung cancer, of which adenocarcinoma is the most common subtype, is the leading cause of cancer-related mortality worldwide. Activating mutations in oncogenic KRAS account for approximately 25% of all lung adenocarcinoma cases, and for these tumours in particular, prognosis is poor and effective chemotherapies are severely lacking. Alveolar type II (AT2) cells act as the major stem cell population within the alveoli and are known to be key cells of origin of lung adenocarcinoma, but the molecular mechanisms and early cellular transformation events that drive their tumourigenesis remain elusive. Using a novel, oncogene-associated multi-colour reporter mouse model, I aim to label and track AT2 cells harbouring Kras mutations and compare their behaviour to wildtype AT2 cells. By analysing individual AT2 cell-derived clones over time, I intend to shed physiological insight into the initial steps of tumourigenesis and determine how dynamic cell-to-cell interactions present between mutant AT2 cells and their associated neighbours facilitate tumour propagation. Collectively, this work will help to devise early detection strategies and identify novel therapeutic targets for the treatment of lung adenocarcinoma, whilst simultaneously highlighting the mechanisms by which lung stem cell function can be hijacked during early disease.

    more_vert
  • Funder: WT Project Code: 217341
    Funder Contribution: 99,812 GBP

    Extracellular vesicles (EVs) are increasingly recognised as mediators of inter-tissue cross talk in health and disease. However, understanding of the mechanisms that determine tissue specific uptake, or tropism of EVs is incomplete. This proposal aims to identify a model that can address this by generating a cohort of stable isotope labelled mice, isolating EVs from their blood and 'pulse chasing' them in unlabelled recipients via quantitative proteomics. In brief, mice will be fed a diet containing 13C6 Lysine until it is fully incorporated into the entire proteome. They will then be subjected to a physiological stimulus, known to liberate EVs into circulation (exercise). Labelled EVs Isolated from the donors will then be intravenously injected into unlabelled mouse recipients. Since labelled proteins are distinguishable in mass spectrometry based analyses, a comprehensive proteomic screen of recipient tissues will then reveal (a) whether EVs have 'delivered' protein to each specific tissue (b) what specific proteins have been delivered and significantly, (c) which adhesion proteins, such as integrins or tetraspanins have mediated EV organotropism. The goal is therefore to establish this model with a view to applying it to wider contexts to characterise completely tissue specific EV delivery. Extracellular vesicles (EVs) are tiny, protein filled sacs known to transfer biological information from one organ to another in both diseased and healthy states. However, little is known about how this is controlled. One possibility is that it is down to specific proteins expressed on the surface of the EV that essentially delivers it to a certain organ. This project aims to identify these proteins by using EVs from mice fed with a special diet that labels proteins within them. Labelled mice will be exposed to a bout of exercise, known to release EVs into the blood. EVs will then be isolated and injected into non-labelled mice. This will allow us to determine which tissues EVs have been delivered to and, importantly, which proteins have mediated that delivery. Establishing this model will facilitate a wider examination of the importance and specific mechanisms of EV trafficking in health and disease.

    more_vert
  • Funder: WT Project Code: 220085

    Metastasis is the process by which cancer cells migrate from a primary to a secondary tumour site, with 95% of cancer deaths attributed to this metastatic spread. Cancer cells interact with a variety of host cells at the primary tumour location and as they invade other tissues, these interactions increase their survival and metastatic potential. Platelets are the smallest circulating cell type and are often the first cells to escape blood vessels into a growing tumour. As a cancer cell enters the vasculature it becomes further exposed to circulating platelets. Evidence suggests that platelet:cancer cell interactions mediate interactions with innate immune cells, which are beneficial for the survival and metastasis of cancer cells. My PhD project will use translucent zebrafish larvae to live image how platelets (thrombocytes in fish) might be pivotal at several stages of cancer metastasis. Specifically: - Do platelets mediate cancer cell:macrophage/neutrophil interactions at the site of primary tumours and impact tumour angiogenesis? - How might microclots enable innate immune cells to interact with circulating cancer cells to enable their extravasation to a secondary cancer site? - What role do other immune cells, including eosinophils and adaptive immune cells, play in each of these plateletmediated steps?

    more_vert
  • Funder: WT Project Code: 219980

    Our bodies are made of cells positioned relative to each other in order to make functioning tissues and organs. Within each cell is a pair of barrel-shaped structures called centrioles that help form the “skeleton” of each cell, giving the cell structural integrity as well as positioning information. “Top” and “bottom” of each cell is distinct (i.e. the cell is polar), therefore they are able to pattern themselves appropriately to form larger scale structures. My project centres around how centrioles orient themselves within a cell, such that the cell achieves proper polarity allowing certain structures, like cilia, to form in the right place relative to other cells. To do this I will use the Drosophilaembryo which has many centrioles, all aligned with one end facing the cell cortex with each centriole appearing as a ring. By measuring the percentage of oriented ring-like centrioles upon introduction of genetic mutations and injected drugs, I will elucidate the key proteins and/or cellular pathways that keep centrioles oriented, allowing them to then establish and maintain cell polarity.

    more_vert
Advanced search in
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  • Funder: WT Project Code: 212246
    Funder Contribution: 990,352 GBP

    Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway. Plasma membrane proteins destined for degradation are internalised, enter the endosome, and then transit to the lysosome. Many crucial proteins follow this pathway, with epidermal growth factor receptor (EGFR) an exemplar because of its biological and biomedical importance. EGFR transport to the lysosome requires a crucial event; the receptor is ubiquitinated and then enters membrane vesicles that bud into the lumen of the endosome, to form the multivesicular body. The molecular machinery that drives multivesicular body formation must overcome a complex topological problem: it recognises ubiquitinated EGFR on the cytoplasmic face of the endosome, generates vesicles that capture EGFR inside the endosome, but escapes itself. How this works remains mysterious, but we aim to solve it. We will reassemble the machinery from its component parts on artificial endosomes, and dissect biochemically how it envelops EGFR. We will also examine how the machinery is activated by EGFR, ensuring EGFR’s efficient capture.

    more_vert
  • Funder: WT Project Code: 219994

    The neuromesodermal progenitors (NMPs) are a group of cells found in the developing embryo, which form the spinal cord and surrounding muscle. NMPs are present at the tail end of the embryo, first producing the head, then trunk and finally the tail end, changing the genes they express as they do this. A subset of these time-regulated genes includes the HOX genes, named HOX1-HOX13. At early stages, NMPs poised to make the neck express HOX1, while successively later NMPs that make the trunk and tail progressively express more of the genes until HOX13 is expressed in tail tip. Studies removing these genes showed that each one is necessary to make vertebrae of a particular identity. It is unknown whether the expression of HOX genes in NMPs at different times during development is important to set identity. It is currently only possible to make NMPs in culture with neck and upper trunk identity. Therefore, I hope to develop a method to make human NMPs which express all the Hox codes. Once we have done this, we will research what is controlling how the cells gain Hox identity. Finally, I will research if HOX code controls NMP differentiation when placed into embryos.

    more_vert
  • Funder: WT Project Code: 220025

    The transcription of almost all genes occurs via random transitions between active and inactive gene states. The net mRNA production is determined by the frequency and size of the resulting random bursts of mRNA synthesis, making gene expression a stochastic process. As a consequence, responses of individual immune cells upon bacterial infection are highly variable, resulting in different infection outcomes. For example, only a subset of innate immune macrophages may accurately recognize and kill invading bacteria. In this project, using mathematical modelling of transcriptional bursting, inference of single-cell genomics and live-cell imaging data, I aim to understand mechanisms involved in coordination of the innate immune responses to pathogen stimulation. In particular, I will study how the foodborne Listeria monocytogenes manipulates the host cell’s gene expression and signalling responses in order to establish a successful infection. I hypothesise that modulation of transcriptional bursting characteristics is a key control mechanism that allows the host to fine-tune its response to pathogen infection, and in turn enables the pathogen to implement its infection strategy. Mechanistic understanding of transcriptional dynamics induced by bacterial infection will inform strategies to improve infection outcomes in the future.

    more_vert
  • Funder: WT Project Code: 220093

    Haematopoietic stem cells (HSCs) have been used for the treatment of diseases including immune deficiencies and metabolic disorders, as well as bone marrow repair after radiation treatment. In order to harvest their full potential, it is essential that we expand our understanding of HSC development and function. A vital part of HSC generation in the developing embryo is the transition of a subset of endothelial cells into blood cells. This occurs under the control of a multitude of factors within the cell and those present in the surrounding environment, the hematopoietic niche. The cell cycle has been shown to be an important involved in the cellular differentiation process, as some cells need to exit the cell cycle in order to undergo the transcriptional and morphological changes associated with differentiation. In my project I will investigate the impact of various factors as cell cycle regulators in this early differentiation of endothelial cells into haematopoietic cells. These studies will employ genetically modified mice, alongside state-of-the-art in-vitro and transcriptional profiling techniques such as single-cell RNA-sequencing. We expect our research to help elucidate the origin of HSCs and therefore contribute to our understanding of how to generate these cells in-vitro.

    more_vert
  • Funder: WT Project Code: 220005

    High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The 5-year survival rate is low, as patients are often diagnosed after cancer cells have spread from the ovary to other parts of the body. Their preferred site to spread to is the omentum, which is the fatty tissue covering the abdomen. The omentum provides an environment, named the metastatic niche, that supports cancer cell migration, growth and survival, enabling a tumour to form. Fibroblasts are a type of cell within the omentum which are partly responsible for forming this environment. They do so through the assembly of a protein fibre meshwork which surrounds the cancer cells, named the extracellular matrix (ECM). However, how fibroblasts in the omentum become able to assemble ECM in a manner which allows cancer cells to thrive is not yet understood. During my PhD project, I aim to develop a better understanding of how fibroblasts assemble ECM in this way to create a suitable environment for tumour formation within the omentum. To achieve this, I plan to use techniques including CRISPR, fluorescence microscopy and BioID in cell lines I will generate from ovarian cancer patient omentum samples.

    more_vert
  • Funder: WT Project Code: 220572

    Background Oxidised LDL (oxLDL) forms a significant component of fatty plaques, or atherosclerotic lesions, that accumulate in coronary artery disease and can cause heart attacks or strokes. We have recently developed an antibody to oxLDL, LO1,that can target atherosclerotic plaques. Approach I aim to harness LO1 and other antibody fragments for targeting of nanoparticles to atherosclerotic plaque. I will develop nanoparticles that are capable of carrying a drug, that will be released when it reaches its destination (i.e. the atherosclerotic plaque). I will produce varying designs with different drugs and targeting agents and aim to demonstrate effective delivery of the nanoparticles. I will test these nanoparticles in mouse models of atherosclerosis, as well as a newly developed original experimental model using an amputated human limb. I will then fill the nanoparticles with the drug and aim to demonstrate a beneficial effect. Expected Impact The novel nanoparticles targeted to atherosclerotic plaque will provide a means of local delivery of drugs directly to diseased areas. This will permit much smaller drug doses to be used, with therefore fewer unwanted side effects. In addition, the drugs can be tailored to an individual, utilising the most suitable drug to treat each patient’s atherosclerotic plaques.

    visibility23
    visibilityviews23
    downloaddownloads18
    Powered by Usage counts
    more_vert
  • Funder: WT Project Code: 220088

    Lung cancer, of which adenocarcinoma is the most common subtype, is the leading cause of cancer-related mortality worldwide. Activating mutations in oncogenic KRAS account for approximately 25% of all lung adenocarcinoma cases, and for these tumours in particular, prognosis is poor and effective chemotherapies are severely lacking. Alveolar type II (AT2) cells act as the major stem cell population within the alveoli and are known to be key cells of origin of lung adenocarcinoma, but the molecular mechanisms and early cellular transformation events that drive their tumourigenesis remain elusive. Using a novel, oncogene-associated multi-colour reporter mouse model, I aim to label and track AT2 cells harbouring Kras mutations and compare their behaviour to wildtype AT2 cells. By analysing individual AT2 cell-derived clones over time, I intend to shed physiological insight into the initial steps of tumourigenesis and determine how dynamic cell-to-cell interactions present between mutant AT2 cells and their associated neighbours facilitate tumour propagation. Collectively, this work will help to devise early detection strategies and identify novel therapeutic targets for the treatment of lung adenocarcinoma, whilst simultaneously highlighting the mechanisms by which lung stem cell function can be hijacked during early disease.

    more_vert
  • Funder: WT Project Code: 217341
    Funder Contribution: 99,812 GBP

    Extracellular vesicles (EVs) are increasingly recognised as mediators of inter-tissue cross talk in health and disease. However, understanding of the mechanisms that determine tissue specific uptake, or tropism of EVs is incomplete. This proposal aims to identify a model that can address this by generating a cohort of stable isotope labelled mice, isolating EVs from their blood and 'pulse chasing' them in unlabelled recipients via quantitative proteomics. In brief, mice will be fed a diet containing 13C6 Lysine until it is fully incorporated into the entire proteome. They will then be subjected to a physiological stimulus, known to liberate EVs into circulation (exercise). Labelled EVs Isolated from the donors will then be intravenously injected into unlabelled mouse recipients. Since labelled proteins are distinguishable in mass spectrometry based analyses, a comprehensive proteomic screen of recipient tissues will then reveal (a) whether EVs have 'delivered' protein to each specific tissue (b) what specific proteins have been delivered and significantly, (c) which adhesion proteins, such as integrins or tetraspanins have mediated EV organotropism. The goal is therefore to establish this model with a view to applying it to wider contexts to characterise completely tissue specific EV delivery. Extracellular vesicles (EVs) are tiny, protein filled sacs known to transfer biological information from one organ to another in both diseased and healthy states. However, little is known about how this is controlled. One possibility is that it is down to specific proteins expressed on the surface of the EV that essentially delivers it to a certain organ. This project aims to identify these proteins by using EVs from mice fed with a special diet that labels proteins within them. Labelled mice will be exposed to a bout of exercise, known to release EVs into the blood. EVs will then be isolated and injected into non-labelled mice. This will allow us to determine which tissues EVs have been delivered to and, importantly, which proteins have mediated that delivery. Establishing this model will facilitate a wider examination of the importance and specific mechanisms of EV trafficking in health and disease.

    more_vert
  • Funder: WT Project Code: 220085

    Metastasis is the process by which cancer cells migrate from a primary to a secondary tumour site, with 95% of cancer deaths attributed to this metastatic spread. Cancer cells interact with a variety of host cells at the primary tumour location and as they invade other tissues, these interactions increase their survival and metastatic potential. Platelets are the smallest circulating cell type and are often the first cells to escape blood vessels into a growing tumour. As a cancer cell enters the vasculature it becomes further exposed to circulating platelets. Evidence suggests that platelet:cancer cell interactions mediate interactions with innate immune cells, which are beneficial for the survival and metastasis of cancer cells. My PhD project will use translucent zebrafish larvae to live image how platelets (thrombocytes in fish) might be pivotal at several stages of cancer metastasis. Specifically: - Do platelets mediate cancer cell:macrophage/neutrophil interactions at the site of primary tumours and impact tumour angiogenesis? - How might microclots enable innate immune cells to interact with circulating cancer cells to enable their extravasation to a secondary cancer site? - What role do other immune cells, including eosinophils and adaptive immune cells, play in each of these plateletmediated steps?

    more_vert
  • Funder: WT Project Code: 219980

    Our bodies are made of cells positioned relative to each other in order to make functioning tissues and organs. Within each cell is a pair of barrel-shaped structures called centrioles that help form the “skeleton” of each cell, giving the cell structural integrity as well as positioning information. “Top” and “bottom” of each cell is distinct (i.e. the cell is polar), therefore they are able to pattern themselves appropriately to form larger scale structures. My project centres around how centrioles orient themselves within a cell, such that the cell achieves proper polarity allowing certain structures, like cilia, to form in the right place relative to other cells. To do this I will use the Drosophilaembryo which has many centrioles, all aligned with one end facing the cell cortex with each centriole appearing as a ring. By measuring the percentage of oriented ring-like centrioles upon introduction of genetic mutations and injected drugs, I will elucidate the key proteins and/or cellular pathways that keep centrioles oriented, allowing them to then establish and maintain cell polarity.

    more_vert