Award details

Defining the role of myosin motor proteins and their cargo adaptors in cytokine secretion

Reference	BB/R001316/1
Principal Investigator / Supervisor	Professor Folma Buss
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Cambridge Institute for Medical Research
Funding type	Research
Value (£)	370,698
Status	Completed
Type	Research Grant
Start date	01/01/2018
End date	28/01/2023
Duration	61 months

Abstract

Cytokines are essential messengers that regulate innate and adaptive immunity. Although cytokine secretion by epithelial and immune cells is a fundamental process, we have only very rudimentary understanding how cytokines are transported, sorted and released from cells. Human aging is characterized by chronic, low-grade systemic inflammation with elevated levels of inflammatory cytokines. Thus treatments to correct age-dependent dysregulation of innate immunity may open new ways to support healthy ageing. In addition, the modulation of cytokine secretion can also induce the clearance of existing bacterial infections through activation of innate immunity. In this proposal we aim to identify the machinery especially the myosin motor proteins that mediate and regulate secretion of different cytokines from human cells. We have extensive experience in the study of myosin motor proteins in intracellular trafficking and protein secretion. We will utilise our knowledge and experience in advanced proteomics and in situ proximity labelling, high-resolution microscopy and cutting-edge cell biology techniques to identify the full repertoire of myosin motors that drive cytokine secretion and to establish the exact function of the different myosins along the exocytic pathway. Finally, we aim to develop inhibitors to target the different classes of myosin motors with roles in cytokine secretion. Our aims are: ->To identify and characterise the myosins with roles in cytokine secretion ->To characterise myosin-associated machinery that mediates cytokine release ->To established the exact role of different myosin-adaptor protein complexes in cytokine release ->To test existing myosin inhibitors and to develop new inhibitors for additional myosin classes This project will provide fundamental and important biological insights into basic immunity and identify novel key regulators of cytokine secretion to support healthy ageing and to combat antimicrobial resistance.

Summary

Inflammation is the body's first line of defense to injury and infection. Cells under attack alert the immune system through the release of chemicals, called cytokines, which activate immune cells to clear the wound from bacteria and heal the tissue. However, under certain conditions the body stays on high alert and the inflammation becomes uncontrolled and chronic. Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging", which is a highly significant risk factor for both morbidity and mortality in elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Thus it is very important to control chronic inflammation and regulate the level of cytokines in our body to ensure healthy ageing. In this study we will investigate the machinery in cells that controls the release of cytokines. The biological cell resembles a miniature factory containing a vast collection of dedicated protein machines. These machines are driven by chemical energy and perform a huge variety of different tasks. For example highly specialysed motor proteins can translocate along filament tracks in a step-by-step motion powered by chemical energy derived from ATP. These motor proteins move cargo between different locations rather like a train running along a railway network to their specific destinations. These nanoscale motors also transport cytokines from their production sites to the cell surface, where they are released. Thus our major aim is to identify drugs that regulate these motors and thereby modify transport and release of cellular cytokines.

Impact Summary

Who will benefit from this research? In addition to the specific academic beneficiaries that have been listed in the section above, the public and wider academic community will benefit from the new knowledge gained on crucial processes in basic cell biology and motor protein function. By studying these "biomotors", we will increase our knowledge on the mechanochemical properties and regulation of these protein machines that is of potential interest to biology, material science and chemistry. This work may create potential spin-offs for sensors, electronics, engineering, but also medicine. Of particular importance and interest for the general public is the increase in knowledge about proteins involved in diseases such as chronic inflammation and dementia. These diseases affect a high percentage of our aging population in the UK and places a heavy burden on our health budget. Therefore the outcome from our work will be of interest to a wide range of health professionals. Myosin motor proteins have been shown to be druggable targets and as part of this project we aim to develop and to design using computational methods specific compounds that are able to target select classes of myosins. Thus sectors of the pharmaceutical industry that develop drugs to treat chronic inflammation and neurological disorders will be interested in the new discoveries and knowledge generated by this work. In the long term patients suffering from these diseases may also benefit and thus there might be a crucial positive impact on improving health, well-being and wealth in the UK. In addition the outcome from this research will improve our knowledge on myosin motor proteins and therefore have an impact on industries in the bionanotechnology field. How might they benefit from this research? 1. Industry: This work will lead to a better understanding of the regulation and function of molecular motor proteins in cytokine secretion. Our work will produce new information on how to regulatemotor/cargo complexes that play important tasks in the delivery of cytokines to the cell surface. Therefore, the basic research outlined in this proposal is likely to have a direct impact upon future strategies for treatment of inflammatory disorders. Myosin motor proteins have been proven to be excellent drug targets and we have established a close collaborations with Dr Boyd from CompChem Solutions Limited based in Cambridge to design and develop new small molecules for regulating myosin motor activity. 2. Academics: At present only two inhibitors for MYO2 and MYO6 are commercially available. Thus inhibitors specific for all 12 different classes of human myosins will allow further research to elucidate the specific cellular roles of different classes of myosin motors. 3. Health care professionals and patients will benefit from work undertaken in this study. Although this proposal focuses on basic research to determine how myosin motor proteins function in cytokine secretion, this work will also advance our understanding how myosin motor dysfunction is linked to neurodegeneration, heart disease and chronic inflammation. As mentioned above the social and healthcare costs of these diseases are enormous and therefore any advances in understanding the underlying mechanisms will impact on the treatment of these diseases and the development of disease specific drugs. This will impact on the well-being and quality of life of patients and their immediate social environment. This can create economic benefits by saving health care costs, to allow healthy ageing but also to boost the UK-based pharmaceutical industry. 4. The General Public will benefit from this research, because it will further our understanding of the causes of disease and therefore demonstrate the benefits of basic research to the wider society.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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