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Professor Doug Brooks 

Position: Professor
Division/Portfolio: Division of Health Sciences
School/Unit: School of Pharmacy and Medical Sciences
Group: SIHR PMB
Campus: City East Campus
Office: R5-13B
Telephone: +61 8 830 21229
Fax: +61 8 830 21087
Email: Doug_dot_Brooks_at_unisa_dot_edu_dot_au
URL for Business Card: http://people.unisa.edu.au/Doug.Brooks
(Doug Brooks is currently on leave - last day on leave is Friday, 24 October 2014)


Professor Doug Brooks is the leader of the Mechanisms in Cell Biology and Disease Research Group at the Sansom Institute for Health Sciences in the School of Pharmacy and Medical Science at the University of South Australia. He has over 30 years experience in medical research and is a Research Professor in Molecular Medicine. His initial research training was in Immunology with a focus on cancer research, involving the immunochemistry of cell surface antigens. For 24 years he worked in the Lysosomal Diseases Research Unit at the Women’s and Children’s Hospital, on a group of genetic diseases called lysosomal storage disorders. The Lysosomal Diseases Research Unit has been responsible for significant health outcomes for this group of disorders, with the development of strategies for early screening, diagnosis and treatment. This research reflects his strong interest in lysosomal cell biology and a desire to develop practical applications in biochemical medicine that benefit patients and the wider community. The Mechanisms in Cell Biology and Diseases Research Group has a series of research themes involving basic and applied medical research on cancer, genetic disease, immunity and the early origins of adult health. These project areas are heavily aligned with the national research priorities of Promoting and Maintaining Good Health, A Healthy Start to Life, Aging well and Preventative Health Care. The Mechanisms in Cell Biology and Disease Research Group's primary objective is to facilitate technological advances that result in research and health outcomes that directly benefit all Australians.


Teaching interests

  • Honours, Pharmacy Honours and Doctorate of Philosophy research programs
  • Immunity: in Physiology Essentials 100 and Molecules to tissues B
  • Molecular Pathology 300

Professional associations

Australian Society of Biochemistry and Molecular Biology

Australian Society of Medical Research


Qualifications

Bachelor of Science: Flinders University of South Australia, Adelaide, South Australia. 1977.

Honours Bachelor of Science: "Studies of naturally-occurring autoimmune responses in mice." School of Biological Sciences at Flinders University, Adelaide, South Australia. 1978.

Doctorate of Philosophy: "Human B cell differentiation." Department of Clinical Immunology, School of Medicine, Flinders University of South Australia. 1982.

Affiliate Associate Professor: Faculty of Health Sciences, University of Adelaide (Affiliated through the Department of Paediatrics at the Women’s and Children’s Hospital). 2001-2015.

Professor of Molecular Medicine, Sansom Institute, School of Pharmacy and Medical Science, University of South Australia. 2006-2015.


Research interests

  • My research is focused on altered endosome-lysosome biogenesis in cancer, immune and mental retardation disorders. These project areas are linked by commonality in the endosome-lysosome cell biology and related pathogenesis. For example, the current research focus on innate immune antimicrobial peptide secretion involves similar molecular mechanism to neurotransmission and secretion from cancer cells. The specific objectives of my research are to: Develop methods for the early diagnosis and accurate prognosis of prostate and breast cancers; Define the molecular mechanism of innate immune secretion; Determine the critical link between lysosomal storage and altered neurotransmission. Background: Endosomes are membrane bound compartments within eukaryotic cells and can be formed by cell surface invagination, for example during the endocytosis of macromolecules for delivery to lysosomes for degradation. Lysosomes were first described by De Duve in 1955, as acidic organelles containing an array of degradative hydrolases; a discovery that was linked with the primary dysfunction observed in lysosomal storage disorder patients. Endosomes and lysosomes are contiguous with the cell surface and therefore form a functional interface between the cell and its environment. This critical set of organelles is now recognised as having functions in macromolecular degradation, organelle turnover, cellular recycling, energy pathways, phagocytosis, pathogen killing, antigen presentation and immunity, signalling, cell membrane repair, cell division, intracellular transport, secretion and neurotransmission. Any dysfunction in endosome-lysosome organelles will therefore potentially impact on these important cellular functions. The capacity of this organelle system to respond to environmental change may act as an indicator of cellular function and disease and be altered as a result of the specific disease process. Hypotheses: Altered endosome-lysosome biogenesis is integrally involved in cancer, inflammatory and mental retardation disorders. This involvement occurs due to either a primary mutation that alters endosome-lysosome function or as part of a cellular response to another disease process. By understanding the pathophysiology of these important diseases, new diagnostic and therapeutic strategies will be identified. Current research projects include:
  • 1. Investigate basic endosome-lysosome cell biology and develop innovative technologies: Generate facilities that build capacity in cell biology. Through competitive ARC LIEF grant funding and UniSA infrastructure support, basic equipment has been acquired to establish three facilities: Biophysical Characterisation (CD spectrometer; calorimeter; and Biacore), Advanced Intravital Imaging (Zeiss 710 META NLO confocal with FLIM, multiphoton, pulsed laser and spectral capacity; Vivascope with FLIM and Horiba Raman capacity), Non-invasive Analysis (2 specialised IRMS). These facilities directly support my research group as well as other SA researchers. These facilities have been achieved collaboratively with Professors John Wallace (UniA), Mike Roberts (UQ & UniSA), Clive Prestidge (UniSA), Ross Butler (UniSA) and colleagues, with a driving force and management responsibility from the Mechanisms in Cell Biology and Disease Research Group.
  • 2. Targeted long lived luminescent lanthanide ion probes for live cell imaging and the study of endocytic processes (Collaboration with Dr Sally Plush). Recent advances in cell biology require accurate visualisation of biological processes in live cells at the molecular level (e.g. endocytosis, and protein trafficking). The technology to enable this visualisation of cellular processes has been partially facilitated by progress in imaging optics and instrumentation (e.g. state-of-the-art above). However, the field is limited by molecular probes with the ability to: control the method of internalisation and the targeting towards specific organelles; report on the organelle environment in the cell. Lanthanide ion probes are potentially ideal for non-invasive live cell imaging due to their small size, long emission lifetimes, minimal photobleaching and capacity for modulated emission. Hypothesis: By conjugating specific cellular targeting motifs to luminescent lanthanide ion complexes we will be able to control probe internalisation/localisation, enabling studies on the dynamic processes of sub-cellular traffic and both molecular as well as pathway interaction. Aims: 1. Generate a series of long-lived luminescent lanthanide ion probes that are conjugated to specific cellular targeting motifs. 2. Characterise the physical and photophysical properties of these molecular probes. 3. Evaluate the physiological properties of different probes in relation to both sub-compartment localisation and compartment interaction. This project will develop unique molecular probes with the distinctive photophysical properties (spectral analysis) that enable reporting on mechanisms and pathways of cell internalisation, ligand localisation and compartment interaction. For the first time, the dynamic interaction and function of specific endocytic pathways will be monitored in real time, both in vitro and in vivo. The ultimate aim of this research is to develop molecular probes that aid in cancer diagnosis and prognosis.
  • 3. Role of 14-3-3 proteins in regulating the innate immune response (NHMRC 631915; Collaboration with Dr Tetyana Shandala). This is the first in vivo study linking 14-3-3 proteins to innate immunity. 14-3-3 is being investigated as a key regulator for two of the most important events in an innate immune response; phagosome maturation leading to bacterial degradation; and exocytosis, which releases antimicrobial peptides (AMPs). Innate immunity is a highly conserved mechanism that eukaryotic organisms use to protect themselves against environmental challenge. Inappropriate function of innate immunity has been implicated in various high profile diseases including cancer, asthma, atherosclerosis and mental retardation disorders. Therefore, a clear understanding of the molecular mechanisms involved in generating an innate immune response, has great significance. Hypothesis: We hypothesise that the family of 14-3-3 proteins is a novel element of innate immunity, whose role is to inter-regulate two key pathways of innate immunity; phagosome maturation and anti-microbial peptide secretion. Aims: 1. Define the role of 14-3-3 in macrophage bacterial killing and phagosome maturation in hemocytes. 2. Characterise the involvement of 14-3-3 in the exocytosis of antimicrobial peptides from hemocytes. 3. Investigate the inter-relationship and cause of defective vesicle traffic in 14-3-3 deficient immune response tissues. Significance: In this project we will demonstrate that 14-3-3 is a key regulator in multiple pathways of innate immunity, elucidating roles in phagosome maturation and secretion. By identifying the molecular mechanism of 14-3-3 action, we will uncover potential points for therapeutic intervention in major inflammatory diseases where innate immunity is inappropriately regulated.
  • 4. Altered endosome biogenesis in prostate cancer Every year approximately 20,000 Australian men are diagnosed with prostate cancer and more than 3,000 die of this disease. This makes prostate cancer the second largest cause of male cancer deaths and a significant health care issue, particularly in Australia where the incidence of this disease is high. We will investigate a novel aspect of endosome-lysosome cell biology in prostate cancer to identify new biomarkers. The end stage objectives for this project are therefore to develop effective methods for the early detection and prognosis of prostate cancer, which are important as this will have a major impact on patient outcome and survival. There is mounting evidence for a central role for endosome-lysosome compartments in cancer cell biology. Endosomes and lysosomes are directly involved in the critical processes of energy metabolism, cell division and intracellular signalling, and will therefore have a direct role in cancer pathogenesis. The endosome-lysosome system has a specific capacity to respond to environmental change, acting as an indicator of cellular function and will consequently be altered in cancer. Moreover, the endosome-lysosome system has a critical role in controlling the secretion of proteins into extracellular fluids, making it an ideal system to identify new biomarkers that are released from cancer cells. We therefore performed a comprehensive study of endosome-lysosome proteins in a panel of prostate cancer and non-malignant prostate cells (analysing 45 markers in triplicate cultures for multiple cell lines to determine gene expression, protein amount and secretion) and have demonstrated that endosome biogenesis is significantly altered. These changes in vitro have been confirmed with patient data, and we have established that the early endosome vesicular machinery is altered in prostate cancer, showing: 1. Significant increases in early endosome gene expression and protein amount, in multiple prostate cancer compared to non-malignant control cells 2. Altered distribution of early endosome organelles in prostate cancer cells 3. Altered cancer-specific early endosome gene expression in multiple prostate cancer patient datasets 4. Altered histology for early endosome proteins in prostate cancer specimens 5. Significant increases in early endosome protein secretion and concomitant decreases in late endosome protein secretion, from prostate cancer compared to non-malignant cell lines Endosomal proteins therefore have the capacity to discriminate between prostate cancer and controls, in both cell lines and patient data bases, and none of the previously described prostate cancer biomarkers have this specificity. In this NHMRC project grant we will capitalise on these novel findings and determine the mechanism for the altered endosome biogenesis in prostate cancer. By identifying the critical changes in early endosome biogenesis we will be able to develop novel biomarkers that enable effective early detection and prognosis for prostate cancer patients. Hypotheses: 1. There is altered regulation of early endosome biogenesis and function in prostate cancer 2. Endosomal proteins can be used to efficiently discriminate between prostate cancer and normal control cells/tissues/biological fluid Aims: 1. Identify the critical control point(s) for early and late endosome biogenesis that are altered in prostate cancer and determine the effect on biomarker expression and secretion 2. Develop and validate specific immune assays for endosomal proteins and establish a set of endosome biomarkers that enables effective early detection and patient prognosis for prostate cancer patients
  • 5. Role of neuronal architecture and function in lysosomal storage disorder neuropathology (Collaboration with Dr Emma Parkinson-Lawrence, Dr Kim Hemsley and Dr Damien Keating). Intense suffering and early death are common in the lysosomal storage disorders (combined prevalence of 1:5,000 live births) and more than two-thirds of patients are afflicted with progressive neurological dysfunction. The most common lysosomal storage disorder with neuropathology is mucopolysaccharidosis IIIA. There is neither a defined understanding of the basis of this neuropathology, nor an available treatment regimen. In mucopolysaccharidosis IIIA mice the accumulation of abnormal ubiquitin aggregates and multi-vesicular structures have been observed in the cell body and processes of neurons. Hypothesis: The accumulation of storage material in endosome-lysosome organelles disrupts the intracellular architecture of neurons, impacting on vesicular transport and impairing both synaptic function and neurotransmission. Aims: 1. Examine how storage impacts on the morphology and vesicular machinery of primary mucopolysaccharidosis IIIA mouse neurons. 2. Establish whether synaptic vesicle recycling and neurotransmitter release is impaired in mucopolysaccharidosis IIIA dorsal root ganglia (DRG) neurons. 3. Determine whether neuronal synaptic function is restored by enzyme replacement therapy. Significance: This project will investigate the critical link between altered endosome-lysosome function and neuropathology. By defining the impact of lysosomal storage on neuronal cell function, we will gain insight into potential sites for therapeutic intervention. The accumulation of protein aggregates and organelles in the cell body and axons of neurons has been observed in other human neurodegenerative diseases, highlighting the global significance of this research.

Research publications


95. Parkinson-Lawrence EJ, and Brooks DA. (2007) Book Chapter: Lysosomal Biogenesis and Disease. In: Lysosomal Storage Disorders (J. Barranger ed). Springer, CRC Press, Boca Raton, Florida USA. http://www.amazon.com/Lysosomal-Storage-Disorders-John-Barranger/dp/ 0387709088/ ref=sr_1_3/105-6727723-575633?ie=UTF8&s=books&qid=1190004350&sr=8-3

96. Brooks DA, Turner C, Muller V, Hopwood JJ, Meikle PJ (2007) Book Chapter: I-cell disease. In: Lysosomal Storage Disorders (J. Barranger ed). Springer, CRC Press, Boca Raton, Florida USA. http://www.amazon.com/Lysosomal-Storage-Disorders-John-Barranger/dp/ 0387709088/ ref=sr_1_3/105-6727723-4575633?ie=UTF8&s=books&qid=1190004350&sr=8-3

97. Parkinson-Lawrence EJ, Muller VJ, Hopwood JJ and Brooks DA. (2007) N-Acetylgalactosamine-6-sulfatase protein detection in MPS IVA patient and normal control samples. Clinica Chimica ACTA, 377: 88-91.

98. Karageorgos L, Brooks DA, Harmatz P, Ketteridge D, Pollard A, Melville EL, Parkinson-Lawrence E, Clements PR, and Hopwood JJ. (2007) Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy. Molecular Genetics and Metabolism, 90: 164-170.

99. Brooks DA. (2007) Getting into the fold. Nature Chemical Biology, 3: 84-85.

100. Shoubridge C, Cloosterman D, Parkinson-Lawrence EJ, Brooks DA and Gecz J. (2007) Molecular pathology of mutations in the ARX homeobox gene. Genomics, 90: 59-71.

101. Karageorgos L, Brooks DA, Pollard A, Melville EL, Hein LK, Clements PR, Ketteridge D, Swiedler SJ, Beck M, Giugliani R, Harmatz P, Wraith JE, Guffon N, Sá Miranda MC, Teles EL, and Hopwood JJ. (2007) Mutational analysis of 105 mucopolysaccharidosis type VI patients. Human Mutation, 28: 897-903.

102. Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Shoubridge C, Vandeleur L, Smith R, Edkins S, Stevens C, O’Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Hills K, Jones D, Mironenko T, Perry J, Varian J, West S, Widaa S, Teague J, Dicks E, Butler A, Menzies A, Richardson D, Jenkinson A, Shepherd R, Raine K, Moon J, Luo Y, Parnau J, Baht SS, Gardner A, Corbett M, Brooks DA, Thomas P, Parkinson-Lawrence EJ, Porteous M, Sanderson T, Pearson P, Simensen RJ, Skinner C, Hoganson G, Superneau D, Easton DF, Wooster R, Bobrow M, Turner G, Partington M, Stevenson RE, Futreal PA, Schwartz CE, Srivastava AK, Stratton MR and Gécz J. (2007) Loss of function mutations in UPF3B, a member of the nonsense-mediated mRNA decay surveillance complex, cause mental retardation. Nature Genetics, 39: 1127-1133.

103. Mardones GA, Burgos PV, Brooks DA, Parkinson-Lawrence EJ, Mattera R and Bonifacino JS. (2007) The TGN accessory protein p56 cooperates with the GGA adaptors in the biosynthetic sorting of cathepsin D to lysosomes. Molecular Biology of the Cell, 18: 3486-3501.

104. Borlace GN, Butler RN, and Brooks DA. (2008) Monocyte and macrophage killing of Helicobacter pylori: relationship to bacterial pathogenicity factors. Helicobacter, 13:380-387.

105. Brooks DA and Fuller M. (2009) Lysosomal disorders. Wiley Encyclopedia of Chemical Biology. 4: 1-11.

106. Brooks DA. (2009) The endosomal network. International Journal of Clinical Pharmacology and Therapeutics, 47: Suppl 1: S9-S17.

107. Morrison JL, Wang KCW, Brooks DA, and Botting KJ. (2009) Fetal heart growth: Insulin-like growth factor 1 and sex. Expert Reviews in Obstetrics and Gynecology, 4: 1-5.

108. Keep SJ, Borlace GN, Butler RN, and Brooks DA. (2010) Role of immune serum in the killing of Helicobacter pylori by macrophages. Helicobacter, 15: 177-183.

109. Parkinson-Lawrence EJ, Shandala T, Prodoehl M, Plew R, Borlace GN and Brooks DA. (2010) Lysosomal storage disease – revealing lysosomal function and physiology. Physiology, 25: 102-115.

110. Shandala T, Parkinson-Lawrence EJ and Brooks DA. (2010) Protein cotranslational and posttranslational modification in organelles. Encyclopedia of Life Sciences. Copyright © 2010 John Wiley & Sons, Ltd.

111. Jones HF, Burt E, Dowling K, Davidson G, Brooks DA, and Butler RN. (2010) The effect of age on fructose malabsorption in children presenting with gastrointestinal symptoms. Journal of Pediatric Gastroenterology & Nutrition. In press September 2010.

112. Jones HF, Davidson G, Brooks DA, and Butler RN. (2010)Small bowel bacterial overgrowth in children with suspected carbohydrate malabsorption – an under-diagnosed disorder? Journal of Pediatric Gastroenterology & Nutrition, In press 6th December 2010.

113. Jones HF, Butler RN, and Brooks DA. (2010) Fructose transport and malabsorption in humans. American Journal of Physiology - Gastrointestinal and Liver Physiology, In press 6th December 2010.

114. Borlace GN, Jones HF, Keep SJ, Butler RN, and Brooks DA. (2011) Helicobacter pylori phagosome maturation in primary human macrophages. Gut Pathogens, In press 28th February 2011.

115. Shandala T, Woodcock J M, Ng Y, Biggs L, Skoulakis EMC, Brooks DA, and Lopez AF. (2011) Drosophila 14-3-3å has a critical role in anti-microbial peptide secretion and innate immunity. Journal of Cell Science, In press 15th March 2011.

121. Shandala TS, Kakavanos-Plew R, Ng YS, Bader C, Sorvina A, Parkinson-Lawrence EJ, Brooks RD, Borlace G, Prodoehl MJ and Brooks DA. (2012) The regulation of exocytosis. Book chapter, In: Membrane Trafficking. Ed: R Weigert, Intech Publishing, Rijeka, Croatia. Accepted 14th February 2012.

126. Keating DJ, Winter M, Hemsley K, Mackenzie KD, Teo EH, Hopwood JJ, Brooks DA, and Parkinson-Lawrence EJ. (2012) Exocytosis is impaired in Mucopolysaccharidosis IIIA mouse chromaffin cells. Neuroscience, 227: 110-118.

127. Shandala T, Brooks DA. (2012) Innate immunity and exocytosis of antimicrobial peptides. Communicative and Integrative Biology. 5: 214-216.

128. Sorvina A†, Brooks DA†, Ng YS, Bader CA, Weigert R, Shandala T (2013) Bacterial challenge initiates endosome-lysosome response in Drosophila immune tissues. Intravital, 2: 1-12. †equal first authors.

130. Shandala T, Lim C, Sorvina A, and Brooks DA. (2013) Developing an in vivo Drosophila model of bacterial infection to image phagocytosis. Cells 2: 188-201.


Expertise for Media Contact

I am able to provide media comment in the following areas of expertise:

Discipline: Biochemistry, Cell Biology

  • Immunochemistry & Cell Biology
  • Endosomes & Lysosomes
  • Cancer cell biology
  • Innate immunity
  • Intracellular neurobiology

Research Degree Supervisor

Professor Doug Brooks is the leader of the Cell Biology of Diseases Research Group at the Sansom Institute for Health Sciences in the School of Pharmacy and Medical Science at the University of South Australia. His initial research training was in Immunology with a focus on cancer research, involving the immunochemistry of cell surface antigens. For 24 years he worked in the Lysosomal Diseases Research Unit at the Women’s and Children’s Hospital, on a group of genetic diseases called lysosomal storage disorders. He has been involved in significant health outcomes for this group of disorders, with the development of strategies for early screening, diagnosis and treatment. This research reflects his strong interest in lysosomal cell biology and a desire to develop practical applications in biochemical medicine that benefit patients and the wider community. The Cell Biology of diseases Research Group has a series of research themes involving basic medical research on genetic disease, cancer, the early origins of adult health, and infection and immunity. These project areas are heavily aligned with the national research priorities of Promoting and Maintaining Good Health, A Healthy Start to Life, Aging well and Preventative Health Care. The Cell Biology of Diseases Research Group's primary objective is to facilitate technological advances that result in research and health outcomes that directly benefit all Australians.


Current Projects:

Altered endosome biogenesis in prostate cancer
 Every year approximately 20,000 Australian men are diagnosed with prostate cancer and more than 3,000 die of this disease. This makes prostate cancer the second largest cause of male cancer deaths and a significant health care issue, particularly in Australia where the incidence of this disease is high. We will investigate a novel aspect of endosome-lysosome cell biology in prostate cancer to identify new biomarkers. The end stage objectives for this project are therefore to develop effective methods for the early detection and prognosis of prostate cancer, which are important as this will have a major impact on patient outcome and survival. There is mounting evidence for a central role for endosome-lysosome compartments in cancer cell biology. Endosomes and lysosomes are directly involved in the critical processes of energy metabolism, cell division and intracellular signalling, and will therefore have a direct role in cancer pathogenesis. The endosome-lysosome system has a specific capacity to respond to environmental change, acting as an indicator of cellular function and will consequently be altered in cancer. Moreover, the endosome-lysosome system has a critical role in controlling the secretion of proteins into extracellular fluids, making it an ideal system to identify new biomarkers that are released from cancer cells. We therefore performed a comprehensive study of endosome-lysosome proteins in a panel of prostate cancer and non-malignant prostate cells (analysing 45 markers in triplicate cultures for multiple cell lines to determine gene expression, protein amount and secretion) and have demonstrated that endosome biogenesis is significantly altered. These changes in vitro have been confirmed with patient data, and we have established that the early endosome vesicular machinery is altered in prostate cancer, showing: 1. Significant increases in early endosome gene expression and protein amount, in multiple prostate cancer compared to non-malignant control
Investigate basic endosome-lysosome cell biology and develop innovative technologies
 Targeted long lived luminescent lanthanide ion probes for live cell imaging and the study of endocytic processes (Prof Doug Brooks & Dr Sally Plush).
Recent advances in cell biology require accurate visualisation of biological processes in live cells at the molecular level (e.g. endocytosis, and protein trafficking). The technology to enable this visualisation of cellular processes has been partially facilitated by progress in imaging optics and instrumentation (e.g. state-of-the-art above). However, the field is limited by molecular probes with the ability to: control the method of internalisation and the targeting towards specific organelles; report on the organelle environment in the cell. Lanthanide ion probes are potentially ideal for non-invasive live cell imaging due to their small size, long emission lifetimes, minimal photobleaching and capacity for modulated emission.
Hypothesis: By conjugating specific cellular targeting motifs to luminescent lanthanide ion complexes we will be able to control probe internalisation/localisation, enabling studies on the dynamic processes of sub-cellular traffic and both molecular as well as pathway interaction.
Aims: 1. Generate a series of long-lived luminescent lanthanide ion probes that are conjugated to specific cellular targeting motifs. 2. Characterise the physical and photophysical properties of these molecular probes. 3. Evaluate the physiological properties of different probes in relation to both sub-compartment localisation and compartment interaction.

This project will develop unique molecular probes with the distinctive photophysical properties (spectral analysis) that enable reporting on mechanisms and pathways of cell internalisation, ligand localisation and compartment interaction. For the first time, the dynamic interaction and function of specific endocytic pathways will be monitored in real time, both in vitro and in vivo.
Role of 14-3-3 proteins in regulating the innate immune response
 (Dr Tetyana Shandala & Prof Doug Brooks). This project involves the in vivo study of 14-3-3 proteins and their role in innate immunity. 14-3-3 is being investigated as a key regulator for two of the most important events in an innate immune response; phagosome maturation leading to bacterial degradation; and exocytosis, which releases antimicrobial peptides (AMPs). Innate immunity is a highly conserved mechanism that eukaryotic organisms use to protect themselves against environmental challenge. Inappropriate function of innate immunity has been implicated in various high profile diseases including cancer, asthma, atherosclerosis and mental retardation disorders. Therefore, a clear understanding of the molecular mechanisms involved in generating an innate immune response, has great significance.

Hypothesis: We hypothesise that the family of 14-3-3 proteins is a novel element of innate immunity, whose role is to inter-regulate two key pathways of innate immunity; phagosome maturation and anti-microbial peptide secretion.
Aims: 1. Define the role of 14-3-3 in macrophage bacterial killing and phagosome maturation in hemocytes. 2. Characterise the involvement of 14-3-3 in the exocytosis of antimicrobial peptides from hemocytes. 3. Investigate the inter-relationship and cause of defective vesicle traffic in 14-3-3 deficient immune response tissues.

Significance: In this project we will demonstrate that 14-3-3 is a key regulator in multiple pathways of innate immunity, elucidating roles in phagosome maturation and secretion. By identifying the molecular mechanism of 14-3-3 action, we will uncover potential points for therapeutic intervention in major inflammatory diseases where innate immunity is inappropriately regulated.
Role of neuronal architecture and function in lysosomal storage disorder neuropathology
 Dr Emma Parkinson-Lawrence, Dr Damien Keating and Prof Doug Brooks.
Intense suffering and early death are common in the lysosomal storage disorders (combined prevalence of 1:5,000 live births) and more than two-thirds of patients are afflicted with progressive neurological dysfunction. The most common lysosomal storage disorder with neuropathology is mucopolysaccharidosis IIIA. There is neither a defined understanding of the basis of this neuropathology, nor an available treatment regimen. In mucopolysaccharidosis IIIA mice the accumulation of abnormal ubiquitin aggregates and multi-vesicular structures have been observed in the cell body and processes of neurons.

Hypothesis: The accumulation of storage material in endosome-lysosome organelles disrupts the intracellular architecture of neurons, impacting on vesicular transport and impairing both synaptic function and neurotransmission.
Aims: 1. Examine how storage impacts on the morphology and vesicular machinery of primary mucopolysaccharidosis IIIA mouse neurons. 2. Establish whether synaptic vesicle recycling and neurotransmitter release is impaired in mucopolysaccharidosis IIIA dorsal root ganglia (DRG) neurons. 3. Determine whether neuronal synaptic function is restored by enzyme replacement therapy.

Significance: This project will investigate the critical link between altered endosome-lysosome function and neuropathology. By defining the impact of lysosomal storage on neuronal cell function, we will gain insight into potential sites for therapeutic intervention. The accumulation of protein aggregates and organelles in the cell body and axons of neurons has been observed in other human neurodegenerative diseases, highlighting the global significance of this research.




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