NIHRDataInsights/HRCSData huggingface dataset:
Title: Cross-talk between Ajuba and Rac signalling in the stabilization of cadherin adhesion
Funder: Medical Research Council

Abstract: We have evidence that Ajuba plays a role in Rac dynamics, and conversely, Rac/PAK1 signalling modulates Ajuba-dependent junction stabilization. We will address in three Work Packages: 1 - how Ajuba modulates Rac dynamic. We postulate that Ajuba interaction may prevent Rac.GTP hydrolysis or facilitate recruitment of an exchange factor to junctions to activate Rac. Rac GTP loading and intrinsic hydrolysis will be addressed in the presence/absence of wild-type Ajuba or its phosphomimetic (T172D) or non-phosphorylatable (T172A) mutants. Ajuba mutants unable to interact with Rac will be made and tested in vivo for junction stabilization and rescue of Rac activation. As depletion of DOCK180, a Rac GEF, phenocopies Ajuba RNAi, a potential role for DOCK180 in Ajuba-dependent Rac activation by cadherins will be addressed. 2 - how Ajuba reorganizes actin at cadherin complexes. We will address the relative contribution of Ajuba-dependent actin polymerization versus bundling for cadherin stabilization and how Rac/PAK1 signalling influences these two activities. Mutational analysis will identify the F-actin binding sites on Ajuba responsible for polymerization or bundling and the efficiency of these mutants to strengthen cadherin adhesion. The existence of ternary complexes Rac/Ajuba/Actin or Rac/Ajuba/alpha-catenin will be studied as a mechanism to integrate cadherin complexes with actin cytoskeleton. 3 - the relevance of Ajuba in Rac/PAK1 signalling during tumour progression will be tested. Up-regulation of Ajuba protein and phosphorylation levels will be investigated in tumour tissue microarrays and cell lines (primary and metastatic site) and correlated with malignancy and clinical outcome. We will test Ajuba sub-cellular localization in tumours/cell lines (nucleus, junction or focal adhesion) and which cellular process it regulates downstream of Ras/Rac hyper-activation during transformation (proliferation, invasion and/or junction disassembly).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The Ral-RLIP76 (RalBP1) signalling axis: plugging the GAP
Funder: Medical Research Council

Abstract: It is hypothesized that the minimal platform for oncogenic transformation involves abnormal proliferation and suppression of apoptosis. The Ral GTPases are involved in both processes: RalA is required for anchorage-independent proliferation, while RalB is involved in suppression of apoptosis. Thus, a therapeutic agent directed against Ral-controlled pathways would target both supports of this platform and be a powerful treatment to fight cancer. Recently, we have built up a wealth of knowledge on one RalA/B effector protein, RLIP76 (RalBP1), which is known to function aberrantly in multiple cancers. We have solved the structure of RalB in complex with the GTPase binding domain (GBD) of RLIP76 and used RalB mutants to reveal the thermodynamic hot spots in the interaction surface. We have also characterized the ability of RLIP76 to behave as a GTPase activating protein (GAP) for the Rho family of small G proteins. We have solved the structure of the GAP domain of RLIP76 and revealed why this isolated domain has rather poor catalytic activity towards Cdc42 and Rac1. In this new project we will fully characterize the RLIP76 GAP properties: we will identify exactly which regions of RLIP76 are necessary for full, functional GAP activity and we will determine which of the Rho family proteins are true substrates for this GAP. We will investigate the interaction between epsin and RLIP76, which together regulate cell migration and invasion. We will use our structures to design mutants in RLIP76 and epsin1 that disrupt their interaction and will test them in cell-based assays for their ability to suppress RLIP76 mediated migration and invasion. We will also design peptide-based inhibitors of the interaction and test them in the same assays. This multidisciplinary, innovative and strategically important research will reveal the cellular ramifications of these specific protein interactions for RLIP76 function and may also identify new therapeutic targets and/or early drug-leads


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Role of the BAF180 remodelling complex in transcriptional repression and DNA double strand break repair in mammalian cells.
Funder: Medical Research Council

Abstract: Chromatin profoundly impacts on DNA damage responses and other DNA transactions with a cascade of chromatin alterations arising during DNA repair and processes such as transcription. Active genes in the vicinity of DNA double strand breaks (DSBs) are repressed in an ATM-dependent manner, but changes to chromatin structure, including the role of chromatin remodelling enzymes, remain largely uncharacterised. Failure to accurately repair DSBs, particularly in transcriptionally active euchromatin, can lead to chromosomal aberrations and genome instability. We will investigate the mechanism by which chromatin is reorganized to facilitate accurate repair of DNA DSBs in transcriptionally active regions of chromatin. We have discovered that the PBAF chromatin remodelling complex is required for DSB-dependent transcriptional repression. We will investigate the mechanism by which PBAF mediates this function. Using human cell lines, we will monitor DSB repair by assessing g-H2AX foci formation. H2AX is a variant form of the histone H2A and becomes phosphorylated in the vicinity of DSBs. We will develop a ChIP assay to monitor events at a DSB in a transcriptionally active region. This will be exploited to determine the timing and genetic dependence of PBAF recruitment to transcriptionally active DSBs, and to analyse changes to chromatin structure and composition. The BAF180 subunit of PBAF, which is frequently mutated in cancer, is critical for PBAF's role at DSBs. We will undertake a functional analysis of BAF180 using site directed mutagenesis to examine regions of BAF180 required and the molecular mechanisms involved. Also, we will determine whether PBAF-mediated transcriptional repression prevents chromosomal instability by analysing translocation formation. These studies will reveal the mechanisms that control the cross-talk between DSB repair and transcription. Ultimately, this information will lead to greater insight into the biology of tumourigenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Characterization and impact of novel regulators of mitochondrial DNA integrity on tumourigenesis
Funder: Medical Research Council

Abstract: Mitochondrial defects and mitochondrial genomic instability have long been suspected to play an important role in the development and progression of cancer but to date little direct evidence for a functional role of these defects have been elucidated. Mutations in nuclear genes have been shown to give rise to mitochondrial DNA mutations but the mechanism behind this is unclear. To this end, we carried out an siRNA screen to identify novel regulators of mitochondrial DNA stability. We identified a novel role for the nuclear DNA repair and cancer associated genes, MLH1, PMS1 and MeCP2 in maintenance of mitochondrial DNA integrity. Loss of each of these genes results in decreased levels of the mitochondrial genes, Mt-Cot1, Mt-ND2 and Mt-ATPase6. Further analysis has revealed that deficiency in these genes increases susceptibility to oxidative stress and results in differential expression of complexes in the oxidative phosphorylation pathway. Therefore, given the increasing evidence suggesting an involvement of mtDNA stability in the transformation process, we aim to elucidate the mechanism behind this maintenance of mitochondrial DNA, determine the functional implications and elucidate its impact on carcinogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Patient and organisational level variation in delayed diagnosis of cancer.
Funder: Department of Health (England)

Abstract: Diagnosing cancer promptly makes treatment easier and can help to reduce cancer deaths. This realisation underpins many ‘cancer awareness and early diagnosis’ initiatives. However, the potential to improve the promptness by which cancer is diagnosed is likely to vary between patients with different cancers and characteristics. The aim of this NIHR post-doctoral fellowship is to generate evidence that will help to prioritise and tailor cancer awareness and early diagnosis research and policy for patient groups with the greatest potential for improvement. Generating such evidence can in turn help to achieve faster and greater early diagnosis and public health gains.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Adverse health outcomes among survivors of teenage and young adult cancer
Funder: Department of Health (England)

Abstract: The Department of Health and National Cancer Research Institute have all identified a need and priority for accurate information concerning the risk of adverse health outcomes among survivors of cancer diagnosed in teenage and young adulthood. The objective of this study will be to identify subgroups of the ~200,000 survivors diagnosed with cancer age 15-39 years, in England and Wales, between 1971-2006 at substantially increased risk of particular fatal or nonfatal adverse health outcomes. Research findings would aid in counselling, educating and empowering survivors; creating/updating guidelines for clinical follow-up; preparing “survivorship care plans”; educating health-care professionals; evaluating proposals for future treatment protocols; and assessing potential recalls to clinic of subgroups at substantially increased risk.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: A systems genetics analysis of Rho-family GTPase signalling.
Funder: Wellcome Trust

Abstract: The migration of cells is an essential event during development of the embryo and for many functions in the adult organism. For example immune cells have to migrate to sites of infection in order to eradicate bacteria or viruses. Abnormalities of cell migration are also characteristic of disease processes such as inflammatory disease or cancer where the migration of tumour cells is required for tumours to spread from their original site, to new organs in the patient (a process called metastasi s). Importantly, this process of disease dissemination is the cause of the majority (about 90%) of cancer deaths. Migration of cells is controlled by molecules called Rho-family GTPases that act as switches to turn on the components of the migratory machinery in cells. However very little is known about what determines whether a Rho-GTPase is on or off, the aim of my research is to provide a comprehensive understanding of the processes which turn the switches that control migration on or off.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Identifying components of a halting mechanism that controls delamination during epithelial-mesenchymal transition.
Funder: Wellcome Trust

Abstract: A popular saying states that there is a time and place for everything, suggesting there are also wrong times for things. For animal embryos to develop properly, cells have to move to specific places in the embryo body at correct times. For example, the cells that make up certain bones of the face start out near the back of the neck and head. They are capable of movement through a process called epithelial-mesenchymal transition (EMT). However, once these cells are capable of moving, they do not necessarily move right away. They wait for the right time to move; if they do not do so, which sometimes happens, the embryos develop cleft palate, a hole in the roof of the mouth. Even worse, some cancer cells hijack this process to spread around the body, a process that kills. We will use frog, fish, and chick embryos to search for the signal telling cells to move, like the firing of a gun at the start of a race. If we know what this signal is, we can delay cancer cell metastasis and i mprove current cancer therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Deciphering mammalian MST/hMOB1/NDR/LATS tumour suppressor networks.
Funder: Wellcome Trust

Abstract: The development of cancer is a result of uncontrolled multiplication of cells. Normally, to ensure that each tissue is patterned not only to a specific architecture but also to a defined size, multicellular organisms govern the coordination of cell death and multiplication by strict control mechanisms In general, two classes of proteins are major regulators of these two events: (1) tumour suppressor proteins, and (2) proto-oncoproteins. When either tumour suppressor proteins are lost (inactivat ed) or oncoproteins are present in abundance (hyperactivated), the coordination of cell death and multiplication is misbalanced, consequently resulting in cancer development. With this study, I would like to investigate the biological mechanisms underlying the regulation of a selected group of tumour suppressor proteins. My aim is to define and understand the key steps that are essential for the anti-cancer activities of these tumour suppressor proteins. Overall, the precise characterisation of these tumour suppressor networks might open novel avenues in the fight against human cancer. On the long-term, understanding where, how and why these tumour suppressor proteins are required for tumour suppression might also help to establish how far these proteins can be used as read-outs in the detection, prognosis and treatment of cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Defining the role of BRCA1 and associated proteins in suppressing 53BP1-dependent toxic DNA repair.
Funder: Wellcome Trust

Abstract: Every day the DNA in each of our cells is damaged. Fortunately, our cells are protected from this by specialised proteins that repair damaged DNA in many different circumstances. However, when these proteins malfunction as a result of genetic mutations, DNA damage can be mis-repaired forming the additional mutations that lead to human disease and cancer. One important DNA-repair protein is BRCA1, mutations in which pre-dispose women to the most common form of hereditary breast and ovarian cancer s. I propose that BRCA1, together with another protein (Rif1), control the manner in which DNA damage is repaired in our cells, by preventing an error-prone form of DNA repair performed by the 53BP1 protein. A likely consequence of BRCA1 mutations would be the inappropriate repair of damaged DNA by 53BP1, resulting in mutations that trigger the onset of cancer. This work aims to provide a better understanding of the role of BRCA1 in preventing cancer, through examining how it functions to preven t errors during the repair of our DNA. It also aims to understand how 53BP1, a protein that is important for the human immune system, when mis-regulated can lead to the alterations to our cells DNA that lead to cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Identifying mechanisms of mechanosensation in the Drosophila notum that contribute to the control of epithelial junction remodelling.
Funder: Wellcome Trust

Abstract: When two epithelial cells make contact they form a stable cell adhesion complex that finally results in the formation of an epithelium. However when two mesenchymal cells make contact the outcome is completely different: they do not form a permanent adhesion complex and very frequently they move away from each other in a behavior called contact inhibition of locomotion [1]. Intriguingly, cell adhesion molecules such as cadherins are known to be involved in both kinds of cell interaction. The formation and dynamics of the adhesion complex in epithelial cells has been extensively studied [2], but the study of cell-cell interactions and cell adhesion in mesenchymal cells has been rather neglected. The aim of this project is to compare cell adhesion complex formation between epithelial cells and between mesenchymal cells, in order to understand the different outcomes of these two cell interactions. This knowledge would help us to better understand important processes such as epithelial-to-mesenchymal transition and contact inhibition of locomotion; two cell behaviors that are central to both cancer metastasis and cell migration during embryo development. We will use two embryonic cell populations whose behavior has been very well characterized in our lab: neural crest (as a mesenchymal cell type) and placode cells (as an epithelial cell type). Most of the experiments will be performed using Xenopus cells cultured in vitro, but we will also analyze cell behavior in vivo, using zebrafish and Xenopus embryos. The cell adhesion complex has been well characterized in epithelial cells, and several key molecules have been described, such as cadherins, catenins, and elements of the cytoskeleton like actin and myosin. In addition, the regulation of small GTPases, such as RhoA and Rac, has been shown to be essential for the formation and maintenance of epithelial junctions. In this project, we will study in placode (epithelial) and neural crest (mesenchymal) cells: i) the dynamic localization of molecules of the cell adhesion complex during cell contact ii) the dynamics of small GTPases during cell contact and their regulation by elements of the adhesion complex. iii) From the above experiments we expect to find the key elements that regulate the different outcome of epithelial and mesenchymal cell-cell contacts. Based on these results, we will perform functional studies with these molecules in order to change a mesenchymal cell-cell contact into an epithelial interaction and vice versa.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The recruitment of p53 and Mdm2 to the proteasome.
Funder: Wellcome Trust

Abstract: The p53 protein plays a vital part in protecting against the development of cancer and treatments which activate p53 are used in cancer therapy. It is therefore crucial to find out precisely how the activity of p53 is controlled. This will lead to improved insight into the process of cancer development and better therapies. An important way in which the activity of p53 is controlled is through its own breakdown and the breakdown of it regulators. We aim to improve our understanding of ho w p53 and its key regulator Mdm2 are broken down by cells. Protein breakdown participates in many important pathways in normal cells and defects in it can contribute to a number of diseases including cancer. An example of its successful targeting is the use of the drug Bortezomib/Velcade. This inhibits protein breakdown and has had a major impact in the treatment of some types of cancer. It has been used to treat over 100,000 patients and sales of bortezomib have exceeded $1 billion. Th is study will contribute to our general understanding of mechanisms of protein breakdown.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Regulation and function of p52 and Bcl-3 NF-kB subunit complexes.
Funder: Wellcome Trust

Abstract: In humans and other mammals there are five NF-kB proteins that control the response to stress and infection. NF-kB functions by regulating gene activation, the process whereby the information encoded into the gene's DNA is turned into RNA which then provides a template for the synthesis of proteins. Activation of NF-kB results in changes to the activity of hundreds of genes, which determine the nature of the response to the activating event. However, aberrant activation of NF-kB can also resul t in many inflammatory diseases and contribute to the survival and growth of tumours. In this application we plan to further investigate the function of p52, a member of the NF-kB family, together with Bcl-3 a protein with which it interacts and functionally cooperates. We are interested in the mechanisms that control p52 and Bcl-3 activity. These include modifications of p52 that control its association with other NF-kB proteins as well as Bcl-3. We will also create mice containing spec ific mutations in the p52 protein that will allow us to investigate its function in the whole organism. We will use these mice to investigate the ability of p52 to promote the development of specific types of breast cancer


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Modular role of the extra terminal (ET) domain of bromo- and extra terminal (BET) proteins in transcription
Funder: Wellcome Trust

Abstract: This project aims to address the structural role of BET bromodomains in transcription initiation and the implications of disrupting this role in disease, when for example BETs are found fused to the NUT (nuclear protein in testis) protein or when they are associated to viral oncoproteins. To do so I will employ high throughput structural biology techniques to study BET bromodomains, aiming to establish an interaction map with their substrates, understand the molecular details of substrate intera ctions, explain synergy between multiple BET dromodomain modules, explore the molecular and structural basis of their interactions with the positive transcription elongation factor b (P-TEFb), structurally characterize their oncogenic fusions to NUT and probe the molecular and structural basis of their interactions with viral oncoproteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS