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Principles of human development and germ cell program
<p>Specification of human primordial germ cells (hPGCs) occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages also occurs. In combination with human preimplantation embryos, in<em> vitro</em> models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline.</p> <p>For the mec… more
Infection, Immunity and Inflammation
Mathematical genomics and medicine
Institutional Strategic Support Fund PHASE 2 FY2014/16
<ul> <li>Support senior/leadership and early career recruitment in key strategic areas in the Schools of the Biological Sciences and Clinical Medicine</li> <li>Provide early career support for recently appointed lecturers, or equivalent, in the Schools of the Biological Sciences and Clinical Medicine</li> <li>Provide bridging support for early career scientists who are between awards</li> <li>Sup… more
Molecular mechanisms controlling peptide selection for immune recognition.
I have discovered that TAPBPR is a novel MHC class I specific component in the antigen processing and presentation pathway. This work represents a major advance in the field of MHC biology. It is now essential to investigate the specific function of TAPBPR in the immune system in order to understand its role in health and disease. My key research goals are to: 1)Determine the role of TAPBPR in M… more
Functional characterisation of the atypical Notch ligands Dlk1 and Dlk2 and the epigenetic modulation of gene dosage
Virtual Fly Brain: a global informatics hub for Drosophila neurobiology
Drosophila allows unprecedented genetic dissection of a relatively small nervous system that supports complex behaviours. Exploiting this opportunity requires intuitive tools to help users query the expanding knowledge from the literature and bulk image data, in order to generate hypotheses about neural circuits, and find reagents that target the neurons concerned. Virtual Fly Brain (VFB) is the … more
Enhancing the fission yeast model organism database POMBASE and extending the benefits of community annotation.
Using Wellcome Trust funding, we have developed PomBase, a Model Organism Database to support exploratory and hypothesis-driven research using the model eukaryote Schizosaccharomyces pombe (fission yeast). To support literature curation, we have also developed a generic web-based, GMOD-compliant curation tool, Canto, which has been deployed to enable community-led curation, and a fission yeast ph… more
CALR mutations and human myeloproliferative neoplasms.
This application combines studies of patient samples with mouse and cell line models to address two questions: 1) How do CALR mutations influence haematopoietic stem cell (HSC) biology, megakaryopoiesis and myeloproliferative neoplasm (MPN) pathogenesis? 2) What are the consequences of CALR mutations for cytokine signaling and CALR function? These are relevant to two of the Wellcome Trust's Research Challenges - genetics/genomics and aging/chronic disease.
Does enhanced PI3K signalling render APDS patients susceptible to infections by interfering with B cell development and activation?.
Aberrant B cell activity can initiate or aggravate both immunodeficiencies and autoimmunity, and lead to lymphoproliferative disorders. PI3delta (phosphoinositide 3-kinase) is key in the signaling pathways regulating many immune cells, including B and T cells. We have identified patients with a dominant mutation in PI3delta (phosphoinositide 3-kinase ) catalytic subunit, a novel primary antibod… more
Public Engagement Provision.
<p>This proposal is to facilitate creation of a world-leading centre for fundamental and translational stem cell research. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructe… more
Courtship of Drosophila: vibratory signals by the male and their receipt by the female.
I pose the main question (A) and subquestions below (B-E). A What are the mechanisms responsible for planar cell polarity (PCP) and how does PCP help build pattern in animals? Most, perhaps all, cells in epithelial sheets are polarised in the plane of the sheet (PCP), as shown by the patterned orientation of mammalian hairs and insect bristles as well as by the consistent polarity of cellular out… more
Immunogenetics of KIR and HLA-C variants in Ugandan women with disorders of pregnancy.
We have shown that specific combinations of maternal and fetal immune genes predispose to reproductive failure. We will now identify the specific alleles that predispose to reproductive failure in humans. We will correlate, for the first time, maternal and fetal immune genotypes of large cohorts of normal and abnormal human pregnancies with blood flow dynamics at the experimentally inaccessible h… more
Enteroendocrine cell function in diabetes and obesity.
This program will address some of the fundamental unanswered questions about L-cell biology. L-cells produce hormones affecting glucose homeostasis and appetite, and are the target of current drug development programs for type 2 diabetes. The prediction is that stimulating GLP-1 release from L-cells will provide oral therapies that could be used alongside recently-licensed DPPIV inhibitors. Under… more
Coated vesicle adaptors.
Adaptors select cargo for inclusion into different types of coated transport vesicles. The best characterised of the adaptors are the AP-1 and AP-2 complexes, which are associated with clathrin-coated vesicles (CCVs) budding from intracellular membranes and from the plasma membrane respectively. We plan to look for new cargo sorting signals using libraries of random cytoplasmic tails, and for new… more
21st Century Families: Parent-child relationships and children's psychological wellbeing
<p>New pathways to parenthood have recently emerged that did not exist, nor had even been imagined, at the turn of the 21<sup>st</sup> century. Individuals who were previously unknown to each other have begun to meet over the internet with the purpose of having children together; transgender men and women have begun to have children through medically assisted reproduction; single heterosexual men… more
From Cures to Courts of Justice: The Medical Encounter and Social Order in Early Modern Spain
<p>Early modern encounters have mainly been studied as transactions between individual sick people and their healers. This project shifts the focus by placing encounters within the communities that structured early modern lives and the practices and expectations of social order that shaped them. The variety of encounters that took place in the Catholic kingdom of Castile provides an ideal case st… more
Applying causal interventions to brain networks underlying adaptive perceptual decision making.
<p>The contribution of individual brain regions to perception is not static, and is determined both by task experience and particular stimulus demands. To investigate these dynamic contributions, I propose to use non-invasive brain stimulation combined with electrophysiological measurements. This combination will provide a window into the dynamics of causal relationships between behaviour and spe… more