NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterisation of the contribution of the endoplasmic reticulum in peroxisome multiplication.
Funder: Wellcome Trust

Abstract: The goal of my research is to dissect the molecular events that underlie transport of endoplasmic reticulum (ER) membrane constituents to peroxisomes. My working hypothesis is that Pex3 is first inserted into the ER membrane, where it is concentrated into a subdomain, followed by release in the form of a membranous carrier that subsequently fuses with peroxisomes. I use Saccharomyces cerevisiae as model system but I will also explore Drosophila S2 cells as a higher eukaryotic model system to s tudy these transport events. We have recently developed novel assays to follow peroxisome multiplication and ER-to-peroxisome transport. These assays allow us to study the ER-to-peroxisome transport pathway more easily and to analyse the role of candidate proteins in this pathway. I will use a combination of genetics, biochemical approaches, immuno-gold electron microscopy, live-cell imaging and time lapse microscopy to achieve my objectives: 1) morphological description of the transport inter mediates 2) identification and characterisation of factors involved in the ER-to-peroxisome transport. 3) characterisation of the signals in Pex3 that are required at each stage of its intracellular itinery, 4) identification of additional proteins that follow the same Pex3 route.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Macromolecular assemblies and mechanisms of DNA replication and repair.
Funder: Wellcome Trust

Abstract: Our genetic blueprint is made of DNA. Over time the information encoded in our DNA becomes randomly altered by unwanted chemical reactions. DNA is so precious that cells have developed many different ways to repair the damage and restore the original message, so that a faithful copy of the DNA can be passed on when cells divide. At the molecular level, dedicated collections of proteins act as the cellular engineers that ensure the integrity of our DNA and its accurate duplication prior to cell division. Our work aims to produce a picture in atomic detail of the way in which these proteins carry out the tasks of maintaining and replicating our genome. The study of the molecular mechanisms underlying such manipulations of our DNA represents important biological knowledge in itself, but it is also of great medical relevance. In fact, it is now clear that common life-treatening conditions such as cancer can be caused by defects in the cellular mechanisms that ensure the correct repair an d replication of DNA. The detailed knowledge of such mechanisms represents our best hope for medical intervention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing research capacity and leadership in East Africa from the KEMRI- Wellcome Trust Research Programme, Kenyq.
Funder: Wellcome Trust

Abstract: This proposal aims to develop health-related research capacity and research leadership in East Africa out of the longstanding Wellcome Trust-funded major overseas programme in Kenya. Its central aim is to enable the KEMRI Wellcome Trust Research Programme to produce a cadre of researchers from Kenya and the East African region who are internationally competitive in developing and leading sustainable research programmes throughout the region. The key goals are (1) To provide a coherent car eer development track for health researchers in East Africa. (2) To specifically target key areas of health related research that need particular strengthening in East Africa: translational research, social science research, and clinical trials (3) To build regional research capacity through developing networks with universities and research centres within the region


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation and transduction of cell polarity.
Funder: Wellcome Trust

Abstract: Nearly all cells are polarised, which means that they are different on one end than the other. These differences are necessary for cells to function appropriately. For example, the skin has an obvious inside and outside, and the polarity of the skin cells is needed to make a tight seal. Nerve cells are another type of cell with obvious polarity: they are long and thin, with different areas to receive and send signals. In addition to its central importance in cell function, cell polarity is als o relevant to human disease as its loss is a critical step in tumour formation. We study how cells become polarised and how they use this information to carry out their functions. Because the ways that cells acquire polarity are very similar in all animals, we can make rapid progress by studying a system where experiments are easy to conduct: the fertilised egg cell of the nematode worm C. elegans. Studying how cells become polarised and how polarity information is used for different cellular processes is crucial for even a basic understanding of development and disease. Our results help the understanding of cell polarity in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A mammalian genetic model for the role of short telomeres in disease.
Funder: Wellcome Trust

Abstract: In humans, the capacity to replenish the genetic material at the ends of our chromosomes (called telomeres) is limited, and often declines with age. As yet, there is no direct evidence whether this age-associated decline in telomeres contributes to our lessened ability to replace and repair tissues with age. These experiments are important to illuminate the reasons for our propensity to develop disease when older. We have developed a model, using the inbred mouse laboratory strain, which mimics the limited telomere maintenance in humans, and will allow us to address whether there is a tissue decline with age that is related to telomere function. Do these animals, like humans, exhibit an increased propensity to cancer or other disorders of cell proliferation as they age? Secondly, we will determine the compounded effects of limiting telomere function and other contributors to genetic instability on the propensity to develop age-associated disease. Finally, we will investigate how the pe rturbation of other genes (using viral infection) might cooperate to enhance or suppress telomere instability. Taken together, it is our goal to uncover mechanisms of telomere maintenance that may have therapeutic implications for the treatment of human disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Ion Channels and Diseases of Electrically Excitable Cells.
Funder: Wellcome Trust

Abstract: What do goats that fall flat on the ground when startled, pigs that shiver themselves to death and people who suffer sudden lethal cardiac arrest have in common? All have mutations in genes that code for ion channels, microscopic protein pores found in all cell membranes. Opening of these pores controls cellular ion movements and their correct operation is essential for cell function. Your ability to see, hear, think, speak, and move your limbs is due to the activity of ion channels in the nerve cells in your brain and the muscles of your limbs. Many human diseases arise from channel malfunction, including diabetes, cystic fibrosis, and epilepsy, and many drugs in clinical use act on ion channels. Our programme seeks to stimulate research on ion channels from molecule to malady. Funds will be used to consolidate old collaborations, forge new ones, develop state-of-the-art facilities and train young scientists in a range of multidisciplinary techniques. This will enhance our unders tanding of ion channels and of how their malfunction causes disease, and lead to the development of new diagnostic methods and therapies. Indeed, OXION studies have already influenced clinical practice for channel diseases such as diabetes and muscle weakness.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Biological and social mechanisms of cardiovascular disease in a transitional rural community in India: Andhra Pradesh Children and Parents Study (APCAPS).
Funder: Wellcome Trust

Abstract: We propose establishing a sustainable framework for building research capacity and policy relevant evidence for the prevention and control of chronic diseases in south Asia. We plan to create a new Wellcome Trust South Asia Centre for Chronic Diseases (the Centre) in India as a collaborative venture between the Public Health Foundation of India (PHFI, www.phfi.org) and constituent colleges of the Wellcome Trust Bloomsbury Centre for Clinical Tropical Medicine. Through hub-and-spokes links bet ween the new Centre and existing research programmes (several of them Wellcome Trust funded) carried out in the region by the applicants, we would a) network with policy makers to determine research priorities and disseminate policy relevant knowledge; b) develop research methodology, a research laboratory service, databases, and research governance; c) create a new large-scale household cohort study building on the existing research in each of the spokes and a new cohort recruited around the Centre; d) conduct translational research, health care evaluation studies, including RCTs, evidence synthesis, health systems and health policy research; and e) mentor and provide career structures for researchers at all stages of their careers.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: The physiology and pathophysiology of unfolded protein responses.
Funder: Wellcome Trust

Abstract: Many common human diseases are caused by failure of proteins to assume or maintain their proper three-dimensional structure. The threat posed by the failure to produce properly folded proteins and by the accumulation of unfolded/misfolded ones triggers rectifying responses aimed at restoring balance between the cellular machinery that folds proteins and the load of unfolded/misfolded proteins it faces. In most circumstances these rectifying unfolded protein responses (UPRs) promote health, howev er, in certain instances of disease-associated protein misfolding, the adaptive features of the UPRs may break down and what would have been a beneficial response turns counter productive. Such phenomena are referred to as failures of homeostasis and counteracting them by pharmacological tuning of cellular signal transduction pathways is the basis for the treatment of important diseases (e.g. hypertension, asthma). This project s overarching goal is to understand the molecular mechanisms involve d in signaling unfolded protein stress with the hope of identifying unique biochemical features that may enable us to tune their activity with pharmacological tools. The pervasive role of protein folding in the physiology and pathophysiology of complex organisms suggests that some of the tools developed by this line of investigation may serve as prototypes for drug development in the future.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the regulation of Polycomb Repressor Complex 1 and its role in epigenetic control of gene expression. .
Funder: Wellcome Trust

Abstract: Cells, the basic unit of all mammals, contain all the information for survival and proliferation. Cell survival and proliferation involve highly regulated processes. One regulatory mechanism is the expression of specific proteins. Different proteins are encoded from unique DNA sequences known as genes. DNA is packaged into chromatin using a complex made up of histones, providing a further level of regulation on top of DNA sequence. Chromatin can be modified to regulate gene expression and prot ein levels in the cell. One complex of proteins that is known to modify chromatin is the polycomb complex PRC1. PRC1 is able to modify a histone and this is associated with gene repression. The PRC1 complex has been shown to play an important role in cell survival and proliferation, through its ability to modify chromatin. How the PRC1 complex is regulated and how it is able to recognise chromatin to modify it is poorly understood. The work described in this proposal is aimed at elucidati ng how PRC1 is regulated and in turn how this regulates gene expression to maintain healthy cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell size homeostasis: pathways that couple growth and division.
Funder: Wellcome Trust

Abstract: A central problem in biology and biomedicine is the regulation of the cell division cycle, the process by which one cell forms two new daughter cells. A network of molecular pathways ensures that the many trillions of cells that make up our bodies divide at the appropriate time. Over the past several years we have used baker s yeast to identify hundreds of genes that control the division decision , which is manifest as the size at which cells divide in all species, from yeast to humans. We have found that the machinery that produces the proteins in the cell (the ribosome) and the organelle that produces all energy for the cell (the mitochondrion), are critical regulators of cell size. We will investigate how these size control networks in yeast work and use this knowledge to decipher how the analogous processes work in human cells. The coupling between cell growth and cell division goes awry in many human diseases including diabetes, mitochondrial disorders, cancer and aging. Once we understand growth and division, we will be in a position to devise means to correct the defects that underlie these and other diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Correlation between the cellular functions of the myosin family of molecular motors and their biochemical & structural properties.
Funder: Wellcome Trust

Abstract: The ability to move and respond to environmental signals is one of the key features of living organisms Movement in the animal and plant kingdoms is mediated by a small group of proteins known as motor proteins, the most familiar of which is the myosin which is responsible for muscle contraction (skeletal and cardiac). There are more than 20 different types of myosin involved in a range of cellular movements from the very fast wing-beat of insects to the slow crawling of individual ameboid cell s such as white blood cells. Other myosins move organelles around inside cells and yet others don t produce movement at all but generate forces inside cells and detect movements such as the response of the very fine stereocillia in our ear to sound waves. While we have a clear idea of how the myosin in muscle does its job we do not know how the same basic motor protein is adapted for such a wide range of behaviours. This is what we plan to find out using novel methods that allow us to follow the fundamental molecular events that myosin goes through on a time scale of < 1/1000 th of a second.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Strengthening community accountability in biomedical research and health delivery.
Funder: Wellcome Trust

Abstract: There is a growing call internationally for citizens to have greater influence on elements of biomedical research and health delivery through voicing their views, which can then be responded to. This is argued to strengthen performance and ethical practice. There are challenges and debates concerning if and how this can be done however. The proposed research will produce new thinking, evidence and recommendations around if, why and how to strengthen community voices in biomedical research and in health delivery in sub-Saharan Africa. The focus of the work will be in Kenya and Tanzania. Literature reviews, an overview of mechanisms used to involve communities, and three detailed case studies (two related to research in both countries and one to health delivery in Kenya) will be conducted. The information gathered will lead to a better understanding of factors influencing the functioning and impact of efforts to strengthen community inputs. Discussion of the findings with communit y representatives, health and research staff, and experts in ethics, health systems, equity, and community development will contribute to national and international papers and presentations on if, why and how communities should be involved in biomedical research and health delivery in future.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular Mechanisms and Control in RNA Polymerase I Transcription and the Impact of Altered rRNA Synthesis on Cell Fate.
Funder: Wellcome Trust

Abstract: Ribosomes are the protein synthesis factories of the cell and contain RNA and protein components. Production of the major ribosomal RNAs (rRNAs) from the DNA that encodes them, involves the process of transcription. This requires the enzymatic activity of the RNA Polymerase I (Pol I) complex of proteins. Uncontrolled Pol I transcription can lead to cell death and has been implicated in the runaway growth characteristic of cancer cells. For Pol I transcription to initiate, Pol I is recruited to a specific region on the rDNA gene by the SL1 complex of proteins. We would like to determine the contributions of each component of the SL1 complex to SL1 function and understand how Pol I recruitment is controlled by the cell. The composition and conformation of Pol I change after the enzyme initiates transcription and we will analyse the transcribing Pol I complex to define these changes and the ability of the protein UBF to effect such changes and increase Pol I transcription output. We will examine how disruption of SL1 and UBF functions can influence cell fate. Information from this research might lead to the identification of novel targets for anti-cancer therapy. (193 words)


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Trace Archive and 1KG DCC.
Funder: Wellcome Trust

Abstract: DNA sequence is generated by complex chemistry processes that gives rise to small fragments of DNA information. The machine read out of these fragments are called traces , and this trace information therefore is the raw data for DNA sequence analysis. By collecting and storing these DNA fragments generated worldwide for research, future scientists can reanalyse data and combine datasets in novel ways. A leading DNA sequencing project, the 1,000 genomes project, is a particular focus as it is combining data from 5 international institutes over 2 years, and therefore needs a common collection and analysis scheme. This proposal provides for this scheme.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at Imperial College London: Support for a Programme Manager and MRes Positions.
Funder: Wellcome Trust

Abstract: We intend to establish a new training programme in experimental medicine for new therapeutics development. We will train aspirant clinician-scientists from a broad range of therapeutic areas in the principles and techniques of Experimental and Translational Medicine. A specific goal is to ensure a future cadre of physicians trained in modern Clinical Pharmacology and Toxicology. Training will cover aspects all along the "critical pathway" for drug development (including exposure to programmes for conventional small molecule and biological agents), but will focus on how the new tools of experimental medicine - imaging, biomarkers, pharmacogenetics and innovative clinical trial design - can be integrated for more efficient, science-led development of new therapies. The training will make use of a translational medicine approach built on a strong foundations in clinical pharmacology (understanding the relationship between drug exposure and drug effect and the importance of investigating individual subject response) and the potential to substantially extend and direct the successful partnership that has been established between Imperial College London and GlaxoSmithKline (GSK) around human genetics, biomarkers, and imaging. The programme will be modular. It will include a 1-year MRes with lectures and supervised projects, 3-Year Clinical PhD Fellowships and two-5-year lectureships (one in Clinical Pharmacology and the other in Toxicology). While most Clinical PhD Fellows are expected to return to the clinical practice of their therapeutic specialty, the programme will equally well prepare clinician-scientists for careers in academia, biotechnology or the pharmaceutical industry. The two lectureships will help support the pedagogical programme and provide for advanced career development with established posts in Clinical Pharmacology and Toxicology, traditional areas of strength in the Faculty of Medicine in Imperial College.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE