Rare disease research in York - University of York · · 2016-03-01Cystic Fibrosis (CF) affects...
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Cystic Fibrosis (CF) affects over 10,000 people in the UK. It is a lifelong condition affecting every organ in the body. CF is also a relative success story – in the 1950s most people died before the age of 5, but now the average life expectancy is 43. We aim that people born with CF today will live to retirement. The adult and paediatric CF teams at York work to provide a high quality, local service. If you want to know more about CF, or the service we offer here in York, go to www.cfyork.org.uk or contact the team on cystic. [email protected] CF is an inherited disease, where a faulty gene means mucus becomes thick and sticky, clogging up the lungs and digestive system, making it hard to breathe and digest food. Sugar is a main energy-source for us, but our cells also build intricate sugar structures, called glycans. Glycans cover the surface of every cell in nature, and affect growth, behaviour and health. They are known to be different in most types of cells, such as embryos, normal human cells and cancer cells. How do we know sugars are important? Disruption of glycans causes a group of rare diseases called Congenital Disorders of Glycosylation (CDG). CDG patients, due to incorrect glycans, suffer from many symptoms, for example: • Poor growth • Muscle problems • Developmental delay • Epilepsy-like fits Artist’s view of a cell’s surface, displaying sugar structures in blue Image: C. Bertozzi We research how glycans are made, what role(s) they play in our bodies, and how this can go wrong in a patient. We are also working on a new diagnostic method. How is neuroblastoma treated? What is neuroblastoma? Research into the causes of neuroblastoma The Evans group studies mechanisms of neuronal development, with a view to understanding how Stage 4S neuroblastoma patients often recover without treatment. On the right are neuro- blastoma cells treated with and without an enzyme that might turn cancer cells back into neurons. Our research is funded by neuroblastoma cancer cells neuroblastoma cells treated with an enzyme that turns them into harmless neurons •surgery and chemo/radiotherapy •20-50 % high risk patients do not respond to therapy •some low risk patients (Stage 4S) are cured when the cancer cells spontaneously revert back to neurons, suggesting a route for new therapies Human T Lymphotropic Virus Cystic Fibrosis (CF) Rett Syndrome Scientists and clinicians at the University of York/ Department of Biology (Biol)/ Centre for Immunology and Infection (CII)/ HYMS and York Teaching Hospital (YTH) tackle important questions to better understand, diagnose and treatment for patients with rare diseases. This poster shows selected examples of these research activities. Please feel free to visit: www.york.ac.uk/biology/research Rett syndrome is a devastating autism spectrum disorder affecting 1 in 10,000 females and is caused by mutations in the X-linked gene encoding Methyl-CpG Binding Protein 2 (MeCP2). The development of mice carrying MeCP2 mutations revealed the presence of neurological phenotypes resembling those observed in Rett syndrome patients. Moreover, reintroduction of MeCP2 into behaviourally affected MeCP2 knockout mice is sufficient to rescue Rett syndrome-like phenotypes raising the exciting possibility that Rett syndrome may be a curable disorder. Darren Goffin (Departments of Biology and Psychology, University of York) has been awarded C2D2/Welcome Trust funds to identify new insights into understanding the mechanisms by which mutations in MeCP2 lead to the manifestation of Rett syndrome. Congenital Disorders of Glycosylation (CDG) •a childhood developmental cancer caused by neuronal stem cells forming tumours instead of sympathetic neurons •UK incidence: ~100 children under 5/year Neuroblastoma Tsetse fly infecting bite Parasite Blood invasion Stage I Encephalitis/Neural Disorders Stage II Investigating parasite proteins for new therapeutic interventions Trypanosoma brucei - African Sleeping Sickness (HAT) The lungs are also infected more easily, and research at York University is helping to understand how bacteria adapt to life in the CF lung. Wildtype OCRL1 Figure 1. OCRL1 mutant flies display black accumulations caused by an immune responses. Observed here in larvae Figure 2. By dissecting flie larvae we can observe the morphology and health of specific neurons and compare these between normal and diseased animals. We particularly study the neuron that connects the brain to the muscle (C) and (D). A B C D The Sweeney lab are now in a position to identify cellular and physiological defects caused by Lowe Syndrome. These experiments are not possible in mammals for reasons of genetic complexity. • Glaucoma and cataracts • Hypotonia (low muscle tone) • Mental retardation ▪ We have generated a Drosophila melanogaster (fruit fly) model of Lowe syndrome Lowe syndrome flies display: • Weak muscles • Reduced brain size • Abnormal neuron characteristics • Activated immune responses • Seizures • accumulation of acid due to kidney dysfunction ▪ Associated with mutations in the OCRL1 gene. Why loss of the OCRL1 gene causes Lowe Syndrome is not known. ▪ Occurs only in males ▪ Found in 1 in 500,000 people ▪ Affects eyes (oculo), brain (cerebro) and kidney (renal) Symptoms include: Lowe Syndrome (Oculocerebrorenal Syndrome) Ten to 20 million people are infected with this retrovirus, which can be caught through unprotected sex, breastfeeding and sharing needles. HTLV remains hidden in most infected. Only ~6% of people develop disease: 3% Adult T Cell Leukemia (ATLL) and 3% HTLV-1 associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 is common in the Caribbean, Japan, Iran, Melanesia, South America, and parts of Africa. In the UK most patients are diagnosed through blood donation services. More than 699 new HTLV diagnoses have been made so far: 65% were women around the age of 52. There are some treatment options for ATLL but no specific treatment for HAM/TSP. North East Retrovirology Referral Centre (NERRC): Dr Fabiola Martin and her team look after HTLV positive people at York Teaching Hospital. HTLV research Laboratory: Dr Fabiola Martin set up the HTLV laboratory at the Centre for Immunology and Infection. Research has been focusing on mucosal and mother to child transmission and has attracted funding from Hull and York Medical School and C2D2/Wellcome Trust. Rare disease research in York Mutations found in Rett syndrome prevent MeCP2 from binding to DNA properly IgG4-Related Disease IgG4-related disease is a newly recognised immune mediated condition. It was only in 2003 when it was recognised as a multiorgan disease. Experts have described it as a “ black crow flying through the dark night” as it escaped recognition through the history of medicine for over a century. Epidemiology of IgG4-RD is not well known because of insufficient awareness. Studies from Japan estimated prevalence of 60 per million. It typically occurs in middle aged and elderly men. Commonly presents as ➢ tumor like swelling of the involved organ ➢ can mimic malignancy, infections or inflammatory disorders ➢ Can involve almost any organ IgG4-RD comprises a spectrum of disorders which were once considered as separate entities. Those at high risk are Pancreatitis of Unknown origin, Bilateral salivary gland swelling, Orbital Pseudotumor, Sclerosing Cholangitis and Retroperitoneal fibrosis. Diagnostic Criteria: Primary: Histology - Lymphoplasmacytic Infiltrate, Storiform fibrosis, Obliterative Phlebitis. Secondary : IgG4+ cells >10/HPF, IgG4+/IgG > 40%, Serum IgG4 > 135mg/dl. Awareness of IgG4-RD is essential as it is a treatable disease. Early recognition can change the management significantly. T Kamisawa et al 2015 MBL Co Ltd Dr Fabiola Martin – CII/HYMS Dr Daniel Ungar – Department of Biology Dr Darren Goffin – Department of Biology Dr Gareth Evans – Department of Biology Dr Rebecca Thomas – Respiratory Medicine YTH Dr Pegine Walrad – CII/Department of Biology Dr Sean Sweeney – Department of Biology Jawad Fazal – Rheumatology YTH Professor Mike Brockhurst – Department of Biology
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Transcript of Rare disease research in York - University of York · · 2016-03-01Cystic Fibrosis (CF) affects...
Cystic Fibrosis (CF) affects over 10,000 people in the UK. It is a lifelong condition affecting every organ in the body.
CF is also a relative success story – in the 1950s most people died before the age of 5, but now the average life expectancy is 43. We aim that people born with CF today will live to retirement.
The adult and paediatric CF teams at York work to provide a high quality, local service. If you want to know more about CF, or the service we offer here in York, go to www.cfyork.org.uk or contact the team on [email protected]
CF is an inherited disease, where a faulty gene means mucus becomesthick and sticky, clogging up the lungs and digestive system, making it hard to breathe and digest food.
Sugar is a main energy-source for us, but our cells also build intricate sugar structures, called glycans. Glycans cover the surface of every cell in nature, and affect growth, behaviour and health. They are known to be different in most types of cells, such as embryos, normal human cells and cancer cells.
How do we know sugars are important?Disruption of glycans causes a group of rare diseases called Congenital Disorders of Glycosylation (CDG). CDG patients, due to incorrect glycans, suffer from many symptoms, for example:• Poor growth• Muscle problems• Developmental delay• Epilepsy-like fits
Artist’s view of a cell’s surface, displaying sugar structures in blue
Imag
e: C
. Ber
tozz
i
We research how glycans are made, what role(s) they play in our bodies, and how this can go wrong in a patient. We are also working on a new diagnostic method.
How is neuroblastoma treated?
What is neuroblastoma?
Research into the causes of neuroblastomaThe Evans group studies mechanisms of neuronal development, with a view to understanding how Stage 4S neuroblastoma patients often recover without treatment. On the right are neuro-blastoma cells treated with and without an enzyme that might turn cancer cells back into neurons.
Our research is funded by
neuroblastoma cancer cells neuroblastoma cells treated with an enzyme that turns them into harmless neurons
•surgery and chemo/radiotherapy •20-50 % high risk patients do not respond to therapy•some low risk patients (Stage 4S) are cured when the cancer cells spontaneously revert back to neurons, suggesting a route for new therapies
Human T Lymphotropic Virus
Cystic Fibrosis (CF)
Rett SyndromeScientists and clinicians at the University of York/ Department of Biology (Biol)/ Centre for Immunology and Infection (CII)/ HYMS and York Teaching Hospital (YTH) tackle important questions to better understand, diagnose and treatment for patients with rare diseases. This poster shows selected examples of these research activities. Please feel free to visit: www.york.ac.uk/biology/research Rett syndrome is a devastating autism spectrum disorder affecting 1 in 10,000 females and
is caused by mutations in the X-linked gene encoding Methyl-CpG Binding Protein 2 (MeCP2). The development of mice carrying MeCP2 mutations revealed the presence of neurological phenotypes resembling those observed in Rett syndrome patients. Moreover, reintroduction of MeCP2 into behaviourally affected MeCP2 knockout mice is sufficient to rescue Rett syndrome-like phenotypes raising the exciting possibility that Rett syndrome may be a curable disorder.
Darren Goffin (Departments of Biology and Psychology, University of York) has been awarded C2D2/Welcome Trust funds to identify new insights into understanding the mechanisms by which mutations in MeCP2 lead to the manifestation of Rett syndrome.
Congenital Disorders of Glycosylation (CDG)
•a childhood developmental cancer caused by neuronal stem cells forming tumours instead of sympathetic neurons•UK incidence: ~100 children under 5/year
Neuroblastoma
Tsetse fly infecting bite
Parasite Blood invasionStage I
Encephalitis/Neural Disorders Stage II
Investigating parasite proteins for new therapeutic interventions
Trypanosoma brucei - African Sleeping Sickness (HAT)
The lungs are also infected more easily, and research at York University is helping to understand how bacteria adapt to life in the CF lung.
Wildtype OCRL1Figure 1. OCRL1 mutant flies display black accumulations caused by an immune responses. Observed here in larvae
Figure 2. By dissecting flie larvae we can observe the morphology and health of specific neurons and compare these between normal and diseased animals. We particularly study the neuron that connects the brain to the muscle (C) and (D).
A B C D
The Sweeney lab are now in a position to identify cellular and physiological defects caused by Lowe Syndrome. These experiments are not possible in mammals for reasons of genetic complexity.
•Glaucoma and cataracts•Hypotonia (low muscle tone)•Mental retardation
▪We have generated a Drosophila melanogaster (fruit fly) model of Lowe syndrome
Lowe syndrome flies display:
• Weak muscles• Reduced brain size
• Abnormal neuron characteristics• Activated immune responses
• Seizures• accumulation of acid due to kidney dysfunction
▪ Associated with mutations in the OCRL1 gene. Why loss of the OCRL1 gene causes Lowe Syndrome is not known.
▪ Occurs only in males▪ Found in 1 in 500,000 people▪ Affects eyes (oculo), brain (cerebro) and kidney (renal)Symptoms include:
Lowe Syndrome (Oculocerebrorenal Syndrome)
Ten to 20 million people are infected with this retrovirus, which can be caught through unprotected sex, breastfeeding and sharing needles. HTLV remains hidden in most infected. Only ~6% of people develop disease: 3% Adult T Cell Leukemia (ATLL) and 3% HTLV-1 associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 is common in the Caribbean, Japan, Iran, Melanesia, South America, and parts of Africa.
In the UK most patients are diagnosed through blood donationservices. More than 699 new HTLV diagnoses have been made so far: 65% were women around the age of 52. There are some treatment options for ATLL but no specific treatment for HAM/TSP.
North East Retrovirology Referral Centre (NERRC): Dr Fabiola Martin and her team look after HTLV positive people at York Teaching Hospital.
HTLV research Laboratory: Dr Fabiola Martin set up the HTLV laboratory at the Centre for Immunology and Infection. Research has been focusing on mucosal and mother to child transmission and has attracted funding from Hull and York Medical School and C2D2/Wellcome Trust.
Rare disease research in York
Mutations found in Rett syndrome prevent MeCP2
from binding to DNA properly
IgG4-Related DiseaseIgG4-related disease is a newly recognised immune mediated condition. It was only in 2003 when it was recognised as a multiorgan disease. Experts have described it as a “black crow flying through the dark night” as it escaped recognition through the history of medicine for over a century.
Epidemiology of IgG4-RD is not well known because of insufficient awareness. Studies from Japan estimated prevalence of 60 per million. It typically occurs in middle aged and elderly men.
Commonly presents as ➢ tumor like swelling of the involved organ➢ can mimic malignancy, infections or inflammatory disorders➢ Can involve almost any organ
IgG4-RD comprises a spectrum of disorders which were once considered as separate entities. Those at high risk are Pancreatitis of Unknown origin, Bilateral salivary gland swelling, Orbital Pseudotumor, Sclerosing Cholangitis and Retroperitoneal fibrosis.
Diagnostic Criteria: Primary: Histology - Lymphoplasmacytic Infiltrate, Storiform fibrosis, Obliterative Phlebitis. Secondary : IgG4+ cells >10/HPF, IgG4+/IgG > 40%, Serum IgG4 > 135mg/dl. Awareness of IgG4-RD is essential as it is a treatable disease. Early recognition can change the management significantly.
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Dr Fabiola Martin – CII/HYMS
Dr Daniel Ungar – Department of Biology
Dr Darren Goffin – Department of Biology
Dr Gareth Evans – Department of Biology
Dr Rebecca Thomas – Respiratory Medicine YTH
Dr Pegine Walrad – CII/Department of Biology
Dr Sean Sweeney – Department of Biology
Jawad Fazal – Rheumatology YTH
Professor Mike Brockhurst – Department of Biology
1. Dr Darren Goffin (Biol) and his group seek to understand the molecular and cellular basis of autism spectrum disorders including Rett syndrome.
2. Dr Fabiola Martin (CII/HYMS) and her team investigate the often hidden virus HTLV and look after infected patients.
3. Dr Daniel Ungar (Biol) and his group focus on glycosylation disorders that are difficult to diagnose as they affect many organs.
4. Dr Rebecca Thomas (YTH) and her team are interested in providing quality care for cystic fibrosis patients, while Professor Mike Brockhurst (Biol) and colleagues research bacteria causing infections in the patients.
5. Dr Sean Sweeney (Biol) and his group study an inherited neurological disease, Lowe Syndrome, using fruit flies.
6. Dr Pegine Walrad (CII/Biol), Professor Deborah Smith (CII/Biol) and colleagues study proteins of the African Sleeping Sickness parasite in search for therapies.
7. Dr Gareth Evans (Biol) and his group seek to understand how the diseased cells of a rare childhood cancer, neuroblastoma, can be turned into healthy neurons.
Please feel free to visit: www.york.ac.uk/biology/research/
