NIHRDataInsights/HRCSData huggingface dataset:
Title: Extending an inter-generational cohort to develop a multimorbidity research platform in rural and urbanising India
Funder: Medical Research Council

Abstract: Despite rapid urbanisation, 65% of India's population resides in rural areas. Socioeconomic development is changing these communities, affecting behaviours (e.g. poor diet) and environmental exposures (e.g. air pollution) alongside prevailing poverty-related risks (e.g. undernutrition), which is predicted to lead to a significant rise in multimorbidity. Local healthcare services, which are largely private, are ill-equipped to manage multimorbidity, leaving rural and peri-urban populations highly vulnerable to catastrophic health expenditures and loss of productivity, potentially inhibiting future development. Our ultimate goal is to establish a multimorbidity research platform for examining the lifecourse and environmental determinants of multimorbidity in rural and urbanising India, and for developing interventions for multimorbidity prevention and management. We propose to do this by extending the Andhra Pradesh Children and Parents Study cohort (N=6,972) and thus capitalising on 30 years of investment from participants, investigators and funders. The current proposal will lay the foundations for the future research platform by: using existing APCAPs data to identify key lifecourse and environmental risk-factors and common clusters of multimorbidity, estimating incident multimorbidity to inform on the required sample size, qualitatively assessing multimorbidity burden and community wishes for future research, and evaluating the feasibility of developing a healthcare surveillance system for future low-cost data collection. Findings from this research will have applications for multimorbidity prevention and management in rural and urbanising India and other populations at similar stages of socioeconomic development.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.4 SURVEILLANCE AND DISTRIBUTION;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Catalysing multimorbidity research in Low and Middle Income Countries through a "community of practice" approach: An India-Brazil-UK Initiative
Funder: Medical Research Council

Abstract: Multimorbidity, the co-existence of two or more chronic conditions in an individual, leads to substantial health care resources use, inferior quality of life and increased premature mortality thus posing enormous challenge for health systems and populations. Despite the unprecedented rise in Non-Communicable diseases in low and middle income countries (LMIC), the domain is sparsely explored in these settings excepting few reports from India, Brazil and South Africa. One of the factors could be the multimorbidity research capability asymmetry and the research-policy-practice ecosystem in LMIC is yet to be cognizant of this burgeoning health care challenge. Our study in India has revealed that one-third of primary care patients have multimorbidity where the challenges are ''horizontal'', integrating not only at the level of the clinical encounter, but also in the co-ordination of services to support patients with multiple problems. We therefore aim to build a South-South Collaboration between India and Brazil with the expert support of UK faculty to develop a "community of practice" on multimorbidity by linking university research hospital, specialists, primary care, public health researchers and health services managers. We plan to adopt a complimentary strategy encompassing: network formation, coalition building within network partners, capacity building of members, and evidence-informed advocacy with key stakeholders for government buy-in. We would develop a contextualized curricular framework for multidisciplinary capacity building in multimorbidity and stimulate the community of practice to collaboratively identify the prioritised research to improve patient outcomes in multimorbidity. We believe that, each country's community of practice established through the project would catalyse multimorbidity research within respective countries and pave path for larger South Asian- South American Network and be a demonstration template for other LMIC to adopt and adapt.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular cell biology of cytoskeletal transport
Funder: Medical Research Council

Abstract: Transport of organelles, vesicles and macromolecules by microtubule-based motors is critical for cellular organisation. Elucidating how these motor complexes operate is not just valuable for understanding fundamental cell biology – there is also clear disease relevance. Impaired cargo transport is increasingly implicated in neurodegenerative disorders and the replication and spread of many pathogenic viruses depends on translocation by microtubule motors. However, the molecular mechanisms that underpin cargo transport by microtubule motors are poorly understood. We are using a combination of genetics (in Drosophila and mammalian cells), in vitro reconstitution, and live cell imaging to shed light on transport mechanisms, as well as their contribution to cell dysfunction in disease and ageing. We have identified key regulatory processes that orchestrate the activity of the minus-end-directed motor, dynein, including during the transport of mRNAs. We have identified novel links between microtubule-based transport and (i) the decline in neuronal function that occurs during ageing and (ii) common neurodegenerative diseases. We have also developed and optimised tools for CRISPR genome engineering in Drosophila, which are being used in several of our own projects as well as by a large number of fly groups around the world. We are currently performing mechanistic analysis of several novel players in microtubule-based transport that we identified in large biochemical and genetic screens. We are also investigating how different mRNAs are sorted to different sites in Drosophila and human cells. We anticipate these studies will shed light on general mechanisms and principles of motor regulation. We anticipate our findings will have therapeutic relevance; for example, it may be possible to target drugs to discrete regions of the cell to maximise their efficacy or to develop agents that stimulate motor activity in order to alleviate problems associated with defective transport in neurodegenerative diseases. We recently collaborated with AstraZeneca to identify candidate small molecule activators of transport, which could be valuable in this regard.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: DNA Motors
Funder: Medical Research Council

Abstract: Structural Maintenance of Chromosomes (SMC) complexes are believed to be the sophisticated machines capable of remodelling chromosome architecture during the essential processes of the cell cycle. Eukaryotes contain three distinct SMC complexes. They form ring-shaped structures and use of ATP hydrolysis to fuel their manipulation in order to change the topology of chromatin fibers. This ability allows SMC complexes to alter local chromatin structure cooperatively to ensure that higher-order manipulation of chromosomes is achieved as required during distinct cellular processes. Although we know the function that distinct SMC complexes play inside cells, how they work at the molecular level, or even what constitutes their activity is not known. SMC function also requires associated activities and factors, including changes in DNA topology (through topoisomerases) and chromatin remodelling. During the last three years, my group has shifted the approach to study SMC complexes by developing novel biochemical tools with a view to dissect the molecular mechanisms of SMC complexes in the next quinquennial. We have successfully purified the three SMC complexes and now plan to study their molecular activities combining in vivo and single molecule techniques. We will continue to use biochemical characterisation of purified proteins using single molecule and in vitro approaches to investigate mechanisms of SMC complex function. These studies will be combined with in vivo analysis in yeast and human cells. Understanding SMC regulation on chromatin and characterising how chromatin remodellers and topoisomerase activities support SMC function will be the priority of the group for the next two to three years.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Maintenance of Germline Genome Stability
Funder: Medical Research Council

Abstract: The repair of damaged DNA is essential in all cells to ensure that the fidelity of the genome is maintained and to prevent mutations accumulating. This is of particular importance in germ cells, the cells that ultimately give rise to sperm and eggs. When these gametes come together they produce a whole new organism with new germ cells, therefore allowing endless propagation of a species. The maintenance of the genetic integrity in the germline is of critical importance to ensure the faithful transmission of the genome from one generation to the next. Failure to accurately maintain genome stability in germ cells has catastrophic consequences for the offspring and to the survival of the species. In contrast, mutations in the germline are an important source of diversity permitting adaptation and evolution. The developing germline undergoes a set of unique processes that pose a threat to genome integrity and pose specific challenges for the DNA repair apparatus. Using a combination of mouse model and in vitro differentiation models we plan to investigate how the DNA repair machinery maintains the genetic integrity of germ cells during their unique lifecycle. We plan to answer three distinct questions; i) When during mammalian germ cell development do mutations arise? ii) How do mammalian germ cells normally suppress mutagenesis? iii) Are there unique sources of DNA damage in germ cells? This will provide us with insights into the basic biology of DNA repair in this critically important but specialised physiological process and help us to understand how the origin of de novo germline mutations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular mechanism of telomere maintenance and the roles of telomeres in human diseases
Funder: Medical Research Council

Abstract: Telomeres are large nucleoprotein assemblies that cap linear eukaryotic chromosomes and protect them from being recognised as DNA breaks. Proper telomere maintenance is essential for genome integrity. Our research aims to understand the mechanisms by which telomeres are maintained. Telomere dysfunction has been strongly implicated in cancers and aging. The proposed research will advance our understanding of how impaired telomere maintenance results in human diseases and cancers. We aim to achieve three major research objectives. The first objective involves elucidating the molecular mechanism of telomerase. Due to the inherent end-replication problem, telomeres are shortened with the number of cell divisions. Telomerase is a specialised reverse transcriptase, which counterbalances this telomere loss by synthesizing the 3’ terminal telomeric repeats. Our recent cryo-EM structure of human telomerase holoenzyme provides unprecedented details into its mechanism at a molecular level and how known human disease mutations affect its structure and function. We also discovered novel subunits. This work opens new avenues for further investigations on telomerase catalytic cycle and its interactions with known and unknown partners. The outcome of this research objective will facilitate drug design studies targeting telomerase. The second objective involves studying aspects of telomerase regulation. In humans, telomerase is recruited to telomeres by shelterin. Shelterin is a protein complex that binds along telomeric DNA and thus plays a crucial role in structuring telomeres. Currently little is known about shelterin structure by itself and how it recruits telomerase to telomeres. To elucidate the underlying mechanism of telomerase recruitment, we are planning to prepare human telomerase and shelterin, reconstitute complexes of telomerase with shelterin and telomeric DNA substrates in vitro and determine their structures by single-particle cryo-electron microscopy (cryo-EM). In addition, we are investigating the roles of a number of other known and unknown factors in telomerase regulation. The third objective aims to elucidate high-order telomere structures to understand how telomere length homeostasis is maintained. It is known that telomerase preferentially extends short telomeres achieve telomere length homeostasis. We want to explore the influence of telomere lengths on the high-order telomere structures, which could explain the observed phenomenon. To achieve this research object, we will employ genome-editing methods to fluorescently label telomeres in human cell lines, which would allow telomeres of different lengths to be visualized by correlative light and electron microscopy (CLEM). We will use electron tomography combined with structures of telomeric complexes obtained by single-particle EM to guide structure determination of telomeres.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The generation and evolution of biological form
Funder: Medical Research Council

Abstract: My lab is interested in the generation of biological form or “morphogenesis”. Our focus is on events at the cellular scale, because the cell is the unit of life and because even large-scale tissue movements are driven by changes in the shape and mechanical properties of individual cells. The most extraordinary and fundamental of all morphogenetic events is cell division: the process by which one cell becomes two. During division, in the space of a few minutes, all the component parts of the cell must be moved apart and partitioned into two daughter cells. This must be done with precision, since errors are associated with diseases like cancer in humans, and frequently cause cell death. Rapid changes in cell organisation, including those that accompany cell division, are brought about by a network of dynamic polymers - the cytoskeleton - which convert chemical energy into force. Strikingly, recent phylogenetic studies have has shown that the key cytoskeletal elements used to drive division and other shape changes in eukaryotic cells (actin, tubulin and ESCRT-III) are ancient proteins, which eukaryotes likely inherited from their archaeal ancestors. Taking advantage of this discovery, in exploring the fundamentals of the division process my lab is looking for similarities and differences in the mechanisms archaea and eukaryotic cells use to divide. Using eukaryotes and archaea (with a focus on Sulfolobus) as model systems, we aim to identify conserved processes, core principles, and to determine how division has changed during the transition from archaea to eukaryotes. We also expect this work to shed light on the process by which the eukaryotic cell first emerged from the symbiosis of an archaeal cell and its bacterial partner – something that remains one of the greatest mysteries in the history of life on earth. Given the fundamental nature of cell division, we also expect this work to improve our understanding of the way the core division machinery functions to aid normal tissue development and homeostasis and, when it goes awry, contributes to the evolution of metastatic cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular Basis of Gene Transcription
Funder: Medical Research Council

Abstract: Correctly regulated, uninterrupted gene transcription is essential for life. Yet, RNA polymerase II (RNAPII), which transcribes all protein-coding genes, is constantly faced with challenges on its way across the gene. One of the main roadblocks to transcription are different types of DNA damage, which cause RNAPII stalling and prevent forward transcription. Just a single RNAPII molecule stalled at a single DNA lesion impairs downstream transcription of an entire gene. It is therefore instrumental to resolve damage-stalled RNAPII complexes, and there are several ways to achieve this: 1) transcription-coupled DNA repair, 2) RNAPII ubiquitylation and degradation, 3) eviction of stalled RNAPII from chromatin, or 4) damage bypass by translesion transcription. Our main area of interest is to understand the mechanistic basis of these processes and relationships between them. Moreover, triggering these events on normally transcribing RNAPII complexes would be detrimental and incompatible with life. We therefore investigate how are these responses directed only at stalled RNAPII molecules, at the correct time and place. To this end, we have evidence that stalled RNAPII is marked by specific post-translational modifications (PTMs). An important goal of the lab is to understand how are these PTMs placed and read to ensure correct processing of stalled RNAPII. We also aim to understand if different types of DNA damage elicit the same or different molecular responses to resolve stalled transcription complexes. When mechanisms for resolving stalled RNAPII are triggered, this can impact the cell’s entire transcriptome. Upon induction of bulky DNA lesions (by UV light for example), a large fraction of RNAPII molecules are ubiquitylated and degraded, leading to depletion of the “free” RNAPII pool and the global shutdown of transcription initiation. While normal cells manage to eventually recover RNAPII protein levels and restart transcription, absence of such a recovery is a hallmark of Cockayne Syndrome. Using genome-wide screens, cell biology and biochemistry, we aim to delineate molecular mechanisms that govern these transcriptional responses to DNA damage in health and disease. Intriguingly, other cellular stresses which do not cause DNA damage (e.g. some viral infections), lead to remarkably similar transcriptional responses, via poorly understood mechanisms. Investigating these pathways, and their overlap with the DNA damage response, will help us understand how the cells evolved robust defence strategies for transcriptional control, to cope with a vast variety of environmental insults.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Nuclear remodelling lab
Funder: Medical Research Council

Abstract: Our lab aims to use and develop cellular structural biology methods to investigate the macromolecular basis of organellar remodelling in space and time, with an emphasis on the reshaping of the nuclear compartment. The cell nucleus is the core organelle which surrounds and protects the genetic material, nevertheless it is able to change position and shape showing an elastic and mechanosensitive nature, which is observed during cell spreading, cell migration, cell differentiation and tissue formation. Our lab is interested in understanding the molecular mechanism of how processes of nuclear remodelling occur. In particular we are interested in the interaction between the different nuclear envelope elements and the cytoskeleton filaments. We aim to reveal details of such concerted organization of macromolecules which shape the nucleus using an integrative structural biology approach, in order to solve the architecture and the oligomerization of key proteins at high resolution. Such information may be important to understand the molecular basis of several disease phenotypes (cancer metastatic progression, progeria, envelopathies, infertility), providing structural information for potential new drug targets. In particular the core research project aims to investigate the macromolecules involved in nuclear remodelling in several model systems including disease phenotypes: - Nuclear architecture in progeria patient cells - Nuclear architecture in iPS cells - Nuclear architecture in stretched/confined cells - Nuclear architecture in the male germline - Nuclear architecture in cancer cells The specific goals of the lab include: - Structural and cell biology investigation of cytoskeleton filaments and binders and of nuclear membrane proteins at different stages of nuclear remodelling, with an emphasis on their oligomerization, interactions and conformational adaptations The final goal aims to unveil how the force which shapes the nucleus is generated from the cytoskeleton elements, LINC protein complexes and other nuclear membrane proteins in the proposed systems. To reach the objectives we plan to combine in vivo cryo-EM techniques with ex vivo cryo-EM, light microscopy, biophysical methods and molecular modelling and simulations to build an integrative 4D model of how macromolecules remodel the nuclear membrane. Methods: - Electron cryo tomography - Correlative light and electron microscopy - Single particle cryo-EM - High resolution light microscopy - Biophysical/biochemical methods - Integrative modelling Devices / tools to allow cell perturbations for structural cell biology investigations are going to be developed and further efforts are going to be made to establish workflows bridging various scales and resolutions at the interface between biology and physics, engineering.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanism of chromosome segregation in mitosis
Funder: Medical Research Council

Abstract: Accurate chromosome segregation during mitosis is critical to ensure each daughter cell inherits the correct complement of chromosomes. Failure to correctly segregate chromosomes results in aneuploidy, a hallmark of cancerous cells. The process of chromosome segregation is mediated by kinetochores, large protein complexes that attach centromeric chromatin to the mitotic spindle, and harness the energy of microtubule depolymerization to move chromosomes to the centrosomes. Additionally, kinetochores ensure the fidelity of chromosome segregation through two inter-dependent correction mechanisms; the tension sensing error correction mechanism, in which aberrant kinetochore-microtubule interactions are resolved, and the spindle assembly checkpoint. Mutations and/or the aberrant expression of proteins that coordinate these mechanisms are associated with a range of cancers. To understand these processes, we undertake a programme to determine the molecular and cellular structure and mechanism of the kinetochore. We focus on reconstituting the entire kinetochore onto centromeric chromatin and microtubules for structural, biochemical and biophysical analysis. This will result in reconstitution of sister chromatid segregation in vitro to simulate the error correction and spindle assembly checkpoint processes. We use cryo-electron tomography to visualize the human and yeast kinetochore-centromere assemblies, and study the yeast spindle pole body to understand the mechanism of microtubule nucleation at centrosomes. We aim to determine atomic-resolution structures of reconstituted recombinant human and budding yeast kinetochore complexes using single particle cryo-electron microscopy. We also seek to understand the spindle assembly checkpoint and error correction checkpoint from a structural, biochemical and biophysical mechanistic perspective.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE