Microglial phagocytic receptors P2Y6 & VNR in brain pathology and therapy

Many brain pathologies, such as brain trauma, infections, stroke, epilepsy and neurodegeneration, are associated with inflammation, which induces a delayed loss of neurons (nerve cells) and synapses (the connections between nerve cells). Microglia are brain cells that regulate inflammation, and when infammed these cells can phagocytose (i.e. eat) neurons and synapses. We and others have found that microglia can eat live neurons and synapses via two types of receptor on their surface: P2Y6 and VNR, and if we block these receptors then we can prevent neuronal and synaptic loss in models of brain pathology.

These are novel and surprising findings, and in this project we want:
1. To determine whether blocking (by drugs or genetics) the phagocytic receptors P2Y6 or VNR is beneficial in a variety of brain disease models.
2. To find novel ways of blocking P2Y6 or VNR that may used as therapy for brain pathology.
3. To determine whether blocking P2Y6 or VNR is beneficial by blocking phagocytosis (eating) of neurons and synapses.
4. To generate genetic knockout mice for P2Y6 and VNR and test whether they are protected against a variety of brain pathologies.

If so, this work may lead on to the development of novel treatments for stoke, trauma, epilepsy, AIDS dementia, Alzheimer's disease and Parkinson's disease.

Many brain pathologies, such as brain ischaemia (stroke), trauma, infections, epilepsy and neurodegeneration, in addition to causing direct damage to neurons, also cause inflammation, which induces a delayed loss of neurons and synapses. Microglia are brain macrophages that regulate inflammation, and when inflamed can phagocytose neurons and synapses. We and others have found that microglia can phagocytose live neurons in models of Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, AIDS dementia, brain trauma, brain infection, epilepsy, stroke and brain development. If we block the P2Y6 or VNR receptors then we can prevent neuronal and synaptic loss in models of brain pathology in culture and in vivo.

These are novel and surprising findings, opening new perspectives on brain pathology and therapy, and in this project we want:
1. To determine whether blocking (by drugs or genetics) the phagocytic receptors P2Y6 or VNR is beneficial in a variety of brain disease models.
2. To find novel ways of blocking P2Y6 or VNR that may used as therapy for brain pathology.
3. To determine whether blocking P2Y6 or VNR is beneficial by blocking phagocytosis of neurons and synapses.
4. To generate genetic knockout mice for P2Y6 and VNR and test whether they are protected against a variety of brain pathologies.

If this work is successful, it would potentially lead on to the development of novel treatments for stoke, trauma, epilepsy, AIDS dementia, Alzheimer's disease, Parkinson's disease and/or other brain pathologies.

1. Scientific & Medical community. Academic beneficiaries will be researchers and medics (in the fields of brain ischaemia, trauma, infections, epilepsy and neurodegeneration) aiming to understand how neurons (and parts of neurons) are lost in brain pathology and how to prevent this. In addition more basic scientists in the fields of biology, neuroscience, inflammation and innate immunity will gain insight into: phagocytosis of host cells and parts of cells, turnover of synapses, and consequences of phagocytosis of cells. We will also generate P2Y6 and VNR knockout mice that will be provided to researchers as an invaluable resources to further research in this field. Output from the project will be disseminated in the normal ways by primary publication, reviews, seminars and conferences. Awareness of concepts and results generated by this project will be promoted by organising a specific conference or session in a conference. GCB has experience of organising several conferences.

2. Industrial and economic beneficiaries. We hope to generate IP for P2Y6 and VNR to be exploited by us or licenced for further drug development. The project aims to verify targets for drug development, to develop novel drugs for these targets and test their efficacy. The University of Cambridge has extensive experience of encouraging, managing and exploiting staff IP, through their technology transfer company, Cambridge Enterprise. Delayed neuronal loss driven by inflammation occurs in many different neurological diseases, including stroke, brain trauma, meningitis, AIDS dementia, epilepsy, MS, PD and AD. Such disease cost the UK economy roughly £50 billion per year (Dementia 2010 report) and the global drugs market for these diseases could be worth £100 billion per year (Pharma 2020 report). If we and others successfully develop drugs to tackle these diseases based on this research, it may make a significant economic impact by a) reducing the economic impact of these diseases and b) selling the drugs.

3. The general public and medical beneficiaries: Delayed neuronal loss driven by inflammation occurs in many different neurological diseases, including stroke, brain trauma, meningitis, AIDS dementia, epilepsy, MS, PD and AD. Such diseases are major causes morbidity in the UK and world. Preventing or alleviating these diseases would have a major impact on the quality of life of a significant fraction of the population (particularly the ageing population). This project presents opportunities to develop treatments to prevent major causes of death and morbidity. This could have impact on the quality of life in the ageing population. The potential major impacts on human health would be through the development of drugs by the pharmaceutical industry as above. However, GCB is also committed to and has extensive experience of public engagement through writing popular science books, journalism, school visits, science festivals and popular lectures. If the project is successful , then we will also communicate this to the wider public for example via articles in New Scientist.

Most of these activities will be undertaken by GCB, but the post-doc (and related PhDs) will be engaged in these activities as much as possible (where appropriate).

Timescale: Communication of results will initially be through publication in the scientific literature and presentations at conferences (years 1-3 and beyond) and then to a wider audiences via secondary articles and presentations (years 2-3 and beyond). If we find that patentable compounds are neuroprotective without significant toxicity in a disease context (years 1-2), we will patent them and seek companies to exploit the IP via Cambridge Enterprise (year 3).