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Results

The Economic Gaze : The World Bank s Influence on Global Public Health. 20 Jan 2015

The World Bank is the largest financial contributor to health related projects and arguably the most important institution in international health cooperation. Symbolically, the World Bank is the arbiter of development norms and meanings combining intellectual prestige and financial power. The 40th anniversary of the Bank's first loan for health provides a timely moment to examine two broad sets of questions of relevance not only to international institutions but also to global public health. Fi rst, what has the Bank contributed to global health over the past 40 years in terms of finance, ideas and networks, and how effective has this contribution been? Second, how has the Bank's increasing involvement as an economic institution transformed how we think about and develop policies to address health? I shall address these two questions through a close examination of five periods in the Bank's history between 1946 and 2014. The project will rely on primary sources from the Bank, includ ing interviews with former and current Bank officials and other knowledgeable stakeholders, archival research at the Bank, WHO and Rockefeller Foundation and relevant secondary sources. The PI is not aware of any other project that has examined the World Bank's contribution to global public health thus filling a major gap in the field. The main proposed output is a monograph with Cambridge University Press. The President of the World Bank (Jim Kim) and head of Global Health (Tim Evans) have agre ed to provide official access to Bank archives and staff.

Amount: £466,406
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Chronic Disease in Sub-Saharan Africa: a critical history of an 'epidemiological transition'. 20 Jan 2015

According to the WHO, Africa is the latest region of the world to be on the cusp of an epidemic of chronic disease, with rising rates of mortality and morbidity from cardiovascular disease, stroke, diabetes, chronic hepatic and renal diseases as well as cancer, mental illness and HIV/AIDS (now widely viewed as a chronic condition). It is projected that by 2015, a quarter of all deaths on the African continent will be caused by such diseases and their concurrence with infectious diseases. High-le vel meetings have produced a plethora of policy documents directed at the very significant challenges that this apparent epidemiological shift poses for already fragile health systems on the continent. A variant of modernisation theory, the historical framework of the epidemiological transition has been widely criticised, but its broad parameters remain at the heart of current policy-making. Accumulating evidence from different regions of Africa, as well as comparative work on India, China, Lati n America and the historical experience of Europe, suggest that this linear model of change may need more radical re-thinking. Recognising the real importance of these issues, this project has two central goals. Firstly, it will take a step back and ask some critical questions about the definitions and measurements of 'chronic' and 'non-communicable' diseases and examine the evidence for their longer history in sub-Saharan Africa. Secondly, through a set of case studies it will provide much-need ed in-depth research on the current situation in sub-Saharan Africa, paying particular attention to 'co-morbidities'.

Amount: £997,498
Funder: The Wellcome Trust
Recipient: University College London

(un)Healthy movement in southern Africa: towards improved responses to communicable diseases. 20 Jan 2015

The Southern African Development Community (SADC) region is associated with both high rates of population mobility and high prevalence of communicable diseases - notably HIV and tuberculosis (TB). Migration and areas characterised by high levels of mobility pose particular challenges for the prevention and treatment of communicable diseases. Migrant populations may also face challenges such as poverty, high rates of gender based violence, and a lack of access to services - including healthcare and justice. These are all contributing factors to various forms of vulnerability, including to ill health. So far appropriate responses that consider cross-border systems and factors which create vulnerability are absent, and responses to ensure treatment continuity and harmonisation of treatment protocols are lacking or are insufficient. In addition, while public health responses are necessary to deal with the transnational nature of communicable disease transmission and treatment, these re sponses are deeply embedded in both regional and national politics around migration. However, the intersections between the regional and local politics of migrant health are rarely explored. This analysis is critical for understanding how regional processes shape migrant marginality, but also how local case-studies can inform national and regional policy. This research project aims to map out and evaluate these inter-connections and to understand how they shape clinical practice and migrant wel l-being and marginality on the ground.

Amount: £692,642
Funder: The Wellcome Trust
Recipient: University of the Witwatersrand

Disorganised Attachment in Contemporary Attachment Theory: a critical analysis of paradigms, debates and applications. 22 Jun 2015

Contemporary Attachment Theory will be a four-year project involving archive research and interviews with 25 leading attachment researchers in the US and UK. It builds on my prior archive research in this area, conducted in the Wellcome Trust Library archives in 2012, and now accepted as peer-reviewed articles. A first goal is to use a sociological perspective to trace developments in the study and conceptualisation of attachment since 1990. I have been offered unprecedented access to all unpubl ished data, manuscripts and notes, and relevant correspondence, from leading attachment researchers with differing perspectives, such as Mary Main and Patricia Crittenden. The research will critically examine contemporary controversies in the field, exploring the conceptualisations of child mental health at stake. It will also assess the implications of different attachment theories for health and welfare interventions with children in the US and UK (e.g. the Circle of Security). A Wellcome PhD student will be requested. Outputs will contribute directly to theory in developmental psychopathology, to the history of discovery in psychological medicine, and to debates regarding interventions using attachment. For the duration of research I have been offered a Visiting position at UC Berkeley, the site of a key archive. In year three, a symposium will bring together researchers from divergent attachment paradigms to integrate knowledge in the discipline. The fourth year will be spent writi ng a textbook on contemporary attachment theory, drawing on the interviews and unpublished material, and with chapters revised and approved by each relevant scholar.

Amount: £16,185
Funder: The Wellcome Trust
Recipient: Northumbria University

Lifestyle, health and disease: changing concepts of balancein modern medicine. 29 May 2015

In 2008, Dr Margaret Chan, Director-General of the WHO, suggested that: `A world that is out of balance in matters of health is neither stable nor secure.' By explaining global health in terms of balance, Dr Chan was mobilising traditional medical beliefs in the relationship between physiological, psychological and political stability and health, from ancient humoral medicine through to modern injunctions to maintain physical balance and fitness, achieve work-life balance, and protect the bala nce of nature in order to safeguard health and well-being. The aim of this research is to analyse ways in which changing notions of balance have shaped scientific and clinical models of healthy lifestyles and to understand the manner in which preoccupations with balance have structured our lives. The central premise is that balance has constituted not only an object for scientific and clinical enquiry, but also a rhetorical construct employed to articulate shifting anxieties about well-bei ng, environmental sustainability, and political security. Research will focus on three overlapping themes: 1. The development, application and reception of scientific theories of, and therapeutic strategies for attaining, bodily balance. 2. Scientific and clinical accounts and patient experiences of coping with mental illness and maintaining work-life balance. 3. Arguments about the relationship between ecological balance and the prevention of chronic diseases, including mental illness, obesity and heart disease. Academic publications, impact activities and the creation of a critical mass of inter-disciplinary researchers will generate a richer understanding of clinical approaches to, and experiences of, changing relationships between lifestyle, health and disease.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Exeter

Global Health Ethics Seminars at WHO HQ, Geneva. 20 Jul 2015

This programme of research will provide a rounded and original analysis of one of the most ambitious efforts at increasing health coverage and equity internationally - the global movement for Primary Health Care (PHC). Developed and run over the course of much of the 1970s and 1980s, this health programme is deserving of detailed attention in a context where a new global movement for PHC is being advocated yet again by the World Health Organization (WHO) Director General, Dr. Margaret Chan (who took up office in 2006 and is expected to be re-elected in 2012). This is, therefore, an ideal time for the preparation of detailed, historically grounded, inter-disciplinary and independent studies of past and current chapters of PHC. Situating these studies in detailed national and local case studies is important, so that they can assist in the development of more context-specific and effective global health policy. The proposed research project will acknowledge the great institutional complex ity of the WHO and other UN organizations such as the UNICEF, as well as national and local governments. Their multifaceted administrative structures ensured that policy goals were interpreted in varying ways and, in turn, meant that there were wide-ranging differences in project implementation. This programme of research will examine the provision of universal healthcare within India, Ceylon/Sri Lanka and Bangladesh; it will also look at the impact of the transnational spread of ideas as a resu lt of work carried out by global heath agencies in South Asia.

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University of York

Understanding astrocyte regional and functional heterogeneity. 07 Jul 2015

The mammalian central nervous system (CNS) shows remarkable regional specialization. This organization, reflected in local and long-range neuronal circuit signaling, underlies both functional complexity of the human brain and vulnerability in certain neurological disorders. It is well recognized that neurons are a diversified population with thousands of sub-types to carry out many specialized functions. In contrast, astrocytes, the most prevalent cell type in the brain, are generally assumed to have homogenous functions across brain regions. However, since astrocytes comprise over 50% of total cells in the brain (Nedergaard et al., 2003, Azevedo et al.,2009), they can be considered as major environmental determinants for local/regional circuits and white matter (Corty & Freeman, 2013, Zhang & Barres, 2010, Han et al., 2013). As such, it is timely and important to challenge the conventional paradigm of astrocyte homogeneity. I propose that astrocyte regional and functional diversity regulates the local in mammals and perhaps invertebrates (Freeman & Rowitch, 2013). Prior work from my lab has-specific shown that astrocytes are allocated according to a spatial-segmental template (Tsai et al.,uit function 2012; Fig. 1). But, a critical unanswered question is whether astrocytes are functionally diversified? We recently reported initial evidence for such heterogeneous function at the single gene level; namely, that ventral spinal cord astrocytes are specialized to encode Sema3a, which is required for sensorimotor circuit integrity (Molofsky et al., 2014). Proving generalized astrocyte regional and functional diversification would defy conventional views and provoke a pervasive reassessment of the roles for astrocytes as key regulators of local neural circuit activity. The proposal will feature interactions between a mammalian and fly lab to: (i) comprehensively determine astrocyte molecular and functional heterogeneity in the vertebrate brain and (ii) investigate evolutionarily conserved astroglial functions in Drosophila. We will develop new transgenic tools and reporters for manipulation of genes required for heterogeneous astrocyte functions during CNS development. The studies are intended to establish whether astrocyte regional and functional diversity is valid as a general neurobiological principle.

Amount: £2,246,774
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fractionating the functions of ventromedial prefrontal cortex of relevance to depression. 07 Jul 2015

I wish to understand how the ventromedial prefrontal cortex (vmPFC) contributes to the regulation of positive and negative emotion. Specific questions are: What are the cognitive functions of these regions relevant to emotion regulation? How do they interact in decision-making to bias behavioural choices? How is that interaction instantiated in cortico-cortical and cortico-subcortical neural circuits? Are these neurocognitive circuits differentially modulated by current pharmacotherapies of depression and how is the balance of control between cortical and subcortical nodes in these circuits modulated by the monoamines? How is the development of these circuits influenced by genetic risk factors for neuropsychiatric disorders? Answers to these questions will inform our understanding of the aetiology and neural basis of the diverse symptoms of depression and guide personalized treatment strategies.

Amount: £2,021,861
Funder: The Wellcome Trust
Recipient: University of Cambridge

How are chromosomes held together by cohesin?. 07 Jul 2015

1. How are chromosomes held together? 2. How does cohesin associate with chromatin and hold sisters together? 3. Mechanism of loading? 4. How is cohesion established? 5. How is dissociation regulated by acetylation? 6. Whatis the role of kinetochore cohesin during meiosis? 7. What is the structure ofcohesin and partners? 8. How does condensin hold together the DNAs of individual chromatids?

Amount: £3,174,432
Funder: The Wellcome Trust
Recipient: University of Oxford

Towards understanding and treatment of MeCP2-related disorders. 07 Jul 2015

Mutations in the MECP2 gene are responsible for two autism spectrum disorders (ASDs): Rett Syndrome[1] (loss of function) and MECP2 Duplication Syndrome[2] (over-expression). Involvement in monogenic ASDs has prompted intensive study of MeCP2 protein, but its functional role remains uncertain. As either too little or too much MeCP2 protein leads to profound intellectual disability, understanding how this protein contributes to brain function is a priority. A prominent view is that MeCP2 is a multifunctional hub protein implicated in diverse pathways. A simpler alternative, suggested by the restricted distribution of Rett syndrome (RTT)-causing mutations, is that MeCP2 is primarily a transcriptional repressor that binds methylated DNA[3] and recruits a co-repressor complex[4]. This research programme is designed to distinguish these hypotheses through a series of experiments that challenge each. It will use the resulting basic knowledge to develop small molecules that may be used therapeutically. The following component questions will be addressed: 1. What are the determinants of MeCP2 binding to chromatin in vivo? Although the protein has been shown to bind methylated DNA, additional determinants have been proposed. 2. Is the ability to bind both DNA and NCoR/SMRT sufficient for MeCP2 function? Our previous work suggests that these two discrete interaction domains are of over-riding functional importance for MeCP2 function. We will create mutations in mice that test this hypothesis. 3. How and why is gene expression affected by varying levels of MeCP2? The reported effects of MeCP2-deficiency on brain gene expression are inconsistent, rangingfrom no clear effects, to mostly activation or mostly repression[5]. We will use homogeneouspopulations of cultured human neurons to resolve this question. 4. Can we identify therapeutic options for treatment of Rett syndrome and MECP2 Duplication Syndrome? Our earlier work established proof-of-principle that Rett syndrome is a reversible condition and therefore in principle curable[6]. So far, however, there are no effective treatments for any MeCP2-related condition. Based on our molecular insights into thebiochemical consequences of specific Rett mutations, we will collaboratively seek small molecules that stabilise or disrupt the structure/interactions of wildtype and mutant MeCP2.

Amount: £2,814,000
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Moving folded proteins across membranes. 07 Jul 2015

The Tat (twin arginine translocation) system, which I co-discovered, is a highly unusual protein transport pathway that is able to export folded proteins across the cytoplasmic membrane of bacteria. It is required for the virulence of many common pathogens. A central question in the Tat field is howthe transporter is able to actively transport folded proteins across the membrane bilayer without significant ion leakage. Tat transport involves threetypes of small integral membrane proteins, multiple copies of which dynamically assemble in the presence of a substrate protein to form a transient transport complex. It is this transport complex that is key to understanding the mechanism of Tat transport. Although we have recently determined high resolution structures of the individual Tat components, the assembled translocation site has been considered to be too ephemeral and unstable to be isolated and studied. In major methodological breakthroughs my group has identified ways of following the behaviour of the complex in real time in living cells, of stalling the transport complex in the assembled state, and of solubilizing the translocation complex from its native membrane environment. I now aim to exploit these advances to answer the key questions about the mechanism of Tat transport: (1) What is the structure of the assembled Tat translocation site? (2) What, based on this structural data, is the physical mechanism of substrate transport across the membrane and of energy transduction to drive transport? (3) What are the component steps in the Tat transport cycle, what are the structural changes occurring at each step, and what molecular features control the interconversion between the steps?

Amount: £1,252,987
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanism and regulatory function of protein coding gene transcriptional termination in mammalian genomes. 07 Jul 2015

The enormous facility with which mammalian genomes can be sequenced has outstripped our understanding of gene function in a genomic context. This disconnect between genomics and gene mechanism is especially evident in understanding how gene transcription units are defined. The major vision behind my proposal is to determine which genes terminate transcription by which mechanism and how this impacts on gene expression. To achieve this we will combine genomic analysis of nascent transcription with mechanistic studies that rely on molecular biological and biochemical analysis. Aims: 1) We will define in molecular detail the common mechanisms that mediate efficient transcriptional termination. 2) We will annotate which termination mechanisms act on which protein coding genes and how this may impact on their expression. 3) Many previously considered ubiquitous termination factors only affect a subset of protein coding genes. We aim to understand why this is the case and how it relates to gene regulation. 4) Transcriptional termination directly interconnects with all other stages of transcription. We will investigate the molecular basis of these interconnections. 5) Loss of termination causes read-through transcription (fused transcripts) a feature ofcancer cells. This suggests that cancer causes breakdown in normal transcription unitdefinition. We aim to better understand why termination is defective in cancer.

Amount: £2,242,936
Funder: The Wellcome Trust
Recipient: University of Oxford

The molecular basis of islet amyloid induced beta-cell death and the inhibition of islet amyloid induced toxicity 07 Jul 2015

Amyloid formation plays a central role in a wide range of devastating diseases, but the mechanism of amyloid formation has yet to be defined in detail for any protein. The nature of the toxic species produced during amyloid formation is controversial and efforts at drug development have been disappointing. This proposal exploits new approaches, developed in our laboratory, to address these critical issues. Our work is focused on islet amyloidosis by the neuropancreatic hormone islet amyloid polypeptide (IAPP, also known as Amylin) and its role in type-2 diabetes (T2D) and beta cell death. Key questions are: (1) What is the mechanism of IAPP amyloid formation?(2) What are the properties of the toxic oligomers produced during islet amyloidosis? (3) What distinguishes toxic from non-toxic oligomers and what factors correlate with toxicity? (4) Why do some amyloid inhibitors protect against toxicity while other promote it? Answering these questions is central to an understanding of amyloidosis and to developing effective therapeutic strategies.

Amount: £1,732,599
Funder: The Wellcome Trust
Recipient: University College London