Dr Nigel Birch

Associate Professor

Molecular, Cellular & Developmental Biology

Phone: 09-3737599 x88239
Rm 228M
Email: n.birch@auckland.ac.nz

Introduction | Our Team | The Laboratory | Research Projects

 

Introduction

Welcome to the Molecular Neuroendocrinology Laboratory in the School of Biological Sciences at the University of Auckland. We are located in downtown Auckland, New Zealand, home of the kiwi and the All Blacks.

The Laboratory of Molecular Neuroendocrinology investigates the molecular and cellular mechanisms regulating key functions in nerve and endocrine cells. Our major goals are to identify and characterize the roles of key serine proteases and serine protease inhibitors in apoptosis, nerve cell regeneration and neurotransmitter and hormone biosynthesis.

We use an interdisciplinary approach in our research, which involves the application of a wide range of molecular, biochemical, and cell biological technologies. We have active collaborations with other scientists at the University of Auckland as well as with international research groups in the USA and Australia.

Our research is funded by the Health Research Council of New Zealand, the Marsden Fund, the Auckland Medical Research Foundation and the University of Auckland.

Contact Us

Molecular Neuroendocrinology Laboratory
School of Biological Sciences
Thomas Building ( Level 4 )
3a Symonds Street
University of Auckland
P.O.Box 92019
Auckland
New Zealand

Phone +64 9 3737599 x8239
fax +64 9 3737414

email: n.birch@auckland.ac.nz

Our Team

Associate Professor Nigel Birch (n.birch@auckland.ac.nz) Research interests: The Laboratory of Molecular Neuroendocrinology investigates the molecular and cellular mechanisms regulating key functions in nerve and endocrine cells.

Leigh Coates Position: Postdoctoral Research Fellow Research interests: Neuroserpin function in neuronal and endocrine cells.

Angela van Diepen Position: Research Technician Research Interests: Neuroendocrine Serpin function

Tet Woo Lee Position: PhD Student Research interests: Serpin structure function studies.

Vicky Tsang
Position: PhD Student
Research interests: Application of adeno-associated viral vectors to alter serpin expression in vivo.

Cecilia van den Hurk
Position: Biomed Honours Student
Research Interests: Serpin cell biology

Sarah Kennedy
Position: Research Technician
Research Interests: Serpin cell biology

The Laboratory

The Molecular Neuroendocrinology Laboratory is located on Level 4 of the Thomas Building (Building 110), Rooms 453, 460, 462 and 464. The MNL Laboratory has all the core equipment required to support molecular and cellular biological research.

Gene expression studies are performed in our tissue culture facility which houses a Class II Biosafety Cabinet and incubators for mammalian and insect cell culture. Several chromatography systems (low to high pressure) are available for protein purification. The main laboratory houses Fuji laser-based and digital CCD imaging facilities for quantitative analysis of radioactive, fluorescent and luminescent signals from various media.

Functional analysis of neuroendocrine cell function also involves fluorescence microscopy using specialized microscopes within SBS or confocal microscopes located in the Biomedical Imaging Research Unit (FoMHS). Neuroendocrine cell morphology is analysed by scanning electron microscopy using a detail located in the Research Centre for Surface and Materials Science, School of Engineering). Proteomics studies utilise the mass spectrometers located in the Proteomics Centre.

SBS also has centralised facilities for protein and DNA sequencing and transmission electron microscopy. The MNL laboratory has excellent computer facilities for image analysis and data quantitation.

Research Projects

Introduction

The Laboratory of Molecular Neuroendocrinology investigates the molecular and cellular mechanisms regulating key functions in nerve and endocrine cells.

Our major goals are to identify and characterize of the roles of key serine proteases and serine protease inhibitors in apoptosis, nerve cell regeneration and neurotransmitter and hormone biosynthesis. Understanding the molecular mechanisms responsible for apoptosis may lead to the development of pharmaceuticals to block or activate cell death associated with various diseases.

Characterization of the interactions between proteases and protease inhibitors during nerve cell growth will contribute to new approaches to rescue damaged nerve cells. Identification of the cellular machinery responsible for the intracellular sorting of enzymes involved in hormone biosynthesis will contribute to our understanding of the fundamental defects associated with plurihormonal syndromes such as diabetes and obesity.

We use an interdisciplinary approach in our research, which involves the application of a wide range of molecular, biochemical, and cell biological technologies. We have active collaborations with other scientists at the University of Auckland as well as with international research groups in the USA and Australia.

Our research is funded by the Health Research Council of New Zealand, the Marsden Fund, the Auckland Medical Research Foundation and the University of Auckland.

Nerve Cell Regeneration

Adult nerve cells normally have a very limited capacity for regeneration after injury. It is believed that the failure of nerve cells to extend axons is not because they are unable to do so, but because they exist in an environment hostile to axon regeneration and lack full trophic support. Neuronal cell regrowth and functional repair after an injury to the brain or spinal cord requires a switch to the conditions found during neuronal development. Axogenesis during development is mediated by high level expression of genes responsible for axon growth promotion and reduced expression of genes that are inhibitory to axon growth. Proteolysis is likely to be an important contributor to the permissive environment for regeneration. Proteases may selectively cleave molecules that either inhibit neurite outgrowth or activate trophic factors that stimulate axonal growth. Excessive proteolytic activity is responsible for degradation of extracellular matrix proteins that contributes to nerve cell death. The correct proteolytic balance is achieved, in part, through regulation by protease inhibitors.

We are investigating the role of the serine protease inhibitor, neuroserpin in nerve cell regeneration and synapse formation. We have recently shown that neuroserpin is expressed in endocrine tissues and can regulate neurite outgrowth in an anterior pituitary corticotrope cell line. We have also prepared recombinant neuroserpin using a Drosophila S2-based expression system for ongoing functional analyses.

Neuroserpin may play a role in nerve cell regeneration by regulating the proteolytic capacity of the extending neuronal growth cone and newly formed synapses. This research has high potential relevance to the treatment of neurological damage and disease for those patients whom axon regeneration is required. Future clinical treatments that enable successful regrowth of fibre tracts in a damaged spinal cord or which are aimed at stimulating axon regrowth in the brain are likely to involve combination therapies tailored to the specific requirements of particular pathways or different times after injury. Such treatments are likely to include growth factors to stimulate axon growth and antibodies to block the actions of inhibitory factors. Manipulation of the neuroserpin:protease axis may have the potential of becoming a new tool might enhance sprouting and elongation of damaged axons.

Apoptosis

Apoptosis is a physiological mechanism that removes unwanted and potentially harmful cells. It is a form of cell suicide that is triggered by a variety of physiological and pathological stimuli. Mis-activation of apoptosis is implicated in many human diseases including neurodegenerative diseases, autoimmune disorders and cancer. Understanding the molecular mechanisms responsible for apoptosis may lead to the development of pharmacological tools to block or activate cell death and treatments for these diseases.

We have recently cloned a new serine protease inhibitor from the rat pituitary gland that we named raPIT5a. Northern blot analysis indicated raPIT5a mRNA expression in a range of tissues, including the adrenal gland and the brain. In situ hybridisation histochemistry revealed raPIT5a mRNA expression in specific cell populations in the rat pituitary gland, adrenal gland, and pancreas. Based on sequence similarities to other intracellular serpins, we predicted raPIT5a may inhibit the pro-apoptotic serine protease granzyme B. We confirmed this experimentally by identification of a stable inhibitory complex between granzyme B and raPIT5a. We have also identified rat natural killer protease-1 (RNKP-1), the rat homologue of granzyme B, and a novel putative serine protease highly similar to granzyme-like protein III (GLP III), which we termed GLP IIIa in pituitary cells (Ref). These data suggest raPIT5a may regulate apoptosis in the pituitary by inhibition of granzyme B or GLP IIIa, or members of the caspase enzyme family, key enzymes in the activation of apoptosis that have similar substrate specificity.

This research project investigates whether an intracellular serine protease inhibitor recently identified in our laboratory can inhibit apoptosis. Our focus is on the nervous system where apoptosis is the terminal step in a number of neurodegenerative conditions. Very recent research from other laboratories suggests inhibition of caspase activity may have a protective role in neurodegenerative conditions. These results re-emphasize the importance of identifying the key regulators of cell suicide, in vivo.

Neurotransmitter and Hormone Biosynthesis

Diabetes, obesity and multiple endocrine disorders are complex conditions that involve the regulation of metabolic processes by biologically active peptides. Disorders in hormone biosynthesis or secretion contribute to the symptoms observed in all these diseases. Many peptide neurotransmitters with different biological activities are synthesized as part of a single multivalent precursor. Differential processing in different regions of the brain leads to the production of unique peptide profiles with different biological effects.

Diabetes, obesity and multiple endocrine disorders are complex conditions that involve the regulation of metabolic processes by biologically active peptides. Disorders in hormone biosynthesis or secretion contribute to the symptoms observed in all these diseases. Many peptide neurotransmitters with different biological activities are synthesized as part of a single multivalent precursor. Differential processing in different regions of the brain leads to the production of unique peptide profiles with different biological effects.

Most peptide hormones and peptide neurotransmitters are synthesized as larger pro-peptide precursors. Biologically active peptides are generated from these precursors in a series of posttranslational enzymatic steps that occur in the regulated secretory pathway. The biologically active peptides are cleaved from the precursor by members of a family of serine proteases, called the subtilisin-like proprotein convertases (SPCs). These enzymes mediate the distinct patterns of post-translational processing observed for many multivalent propeptide precursors. We are interested in how the enzymes involved in peptide processing modulate the cleavage pattern of multivalent precursors. We want to know where in the cell the different cleavage steps take place, how the enzymes are sorted to these compartments and how the activity of the enzymes is regulated. Recent results have identified roles for SPC3 in amylin and cholecystokinin biosynthesis. We have also characterized the posttranslational mechanisms involved in the maturation of SPC3 and identified differential cleavage of the hormone and neuropeptide precursor provasopressin by different molecular forms of SPC3.

Failure of neurons or endocrine cells to synthesize biologically active peptides is detrimental to the whole organism. A mutation in the processing enzyme SPC3 that affects intracellular targeting has been shown to result in human obesity. Indeed this was the first gene mutation identified in humans resulting in obesity. Aberrant processing of neuroendocrine precursors has been linked to diabetes mellitus and diabetes insipidus and may contribute to neurological disease. These results highlight the importance of understanding the molecular mechanisms regulating the cellular trafficking and activation of subtilisin-like serine proteases. Only then will we be able to determine their role(s) in neurological and hormonal disease processes.