Outline of the MIMS lecture course
Important note. This information is provided at the beginning of the year for your guidance and that of your supervisors. It is not intended to be a comprehensive list of contents. Lecturers will all issue their own handouts, and may vary the topics and the order in which they are presented.
Michaelmas Term Metabolism in Health and Disease
Dr G Yeo: Prologue - Diabetes (2)
The aim of the Prologue is to illustrate the molecular basis of medicine, to anticipate the main topics covered in the first term's lectures and to introduce terminology, within the context of diabetes as a common metabolic disease.
Case studies, illustrating typical presentation of diabetes.
Definition of diabetes in terms of hyperglycaemia; diagnosis by glucose tolerance test. Classification, causes and treatment of type 1 (juvenile) and type 2 (maturity onset) diabetes; other forms of diabetes; diabetes in animals.
Historical perspective on Banting and Best and the discovery of insulin.
Acute manifestation of diabetes as a metabolic problem reflecting lack of insulin action. Long term complications of diabetes resulting from chronic hyperglycaemia
Statistics on prevalence of diabetes and obesity and cost implications for health care.
Structure of insulin, as an example of a small protein.
Carbohydrates and lipids as fuels; metabolic pathways for their oxidation.
Introduction to regulation of metabolic pathways by cellular energy charge or hormonal signals ; allosteric regulation and covalent modification of enzymes.
Insulin biosynthesis and secretion.
Actions of insulin on carbohydrate, lipid and protein metabolism.
Insulin receptors and glucose transporters as examples of membrane proteins. Introduction to mechanism of insulin action & signalling via protein kinase cascades. Obesity, insulin resistance and type 2 diabetes; why is insulin action impaired by obesity?
Dr H R Mott: Biological Macromolecules, Protein Structure And Enzyme Catalysis (6)
After an introduction to macromolecules, the lectures concern understanding of the structure of proteins and how the structure governs the function. We will study examples of the structures of medically relevant proteins and enzymes. We will then focus on enzymes, studying how they catalyse reactions and how this activity is controlled.
Introduction to macromolecules. Sugars, nucleic acids and proteins
Protein Structure and function Methods for studying macromolecules.
The levels of protein structure.
The amino acids and peptide bond formation. Prediction of function from sequence information.
Bond formation in the development of protein structure. How proteins fold.
Protein misfolding and disease
The structure of a protein is determined by the amino acid sequence. The role of prosthetic groups and cofactors.
Case study - how protein structure leads to function in haemoglobin. Membrane proteins.
Antibody structure and function.
Enzyme function and control Energetics of enzyme-catalysed reactions
Catalysis of a reaction by transition state stabilisation.
How the structure of an enzyme active site causes catalysis. Classification and characterisation of enzymes.
Michaelis-Menten kinetics. Enzyme inhibition
Alteration of activity by covalent modification. Allosteric control and conformational change. Cooperativity of multimeric enzymes.
Case study - development of HIV protease inhibitors.
Dr R W Broadhurst, Prof. P F Leadlay: Bioenergetics And Metabolism (8)
The metabolic fates of glucose and fat after feeding Importance of blood glucose concentration and insulin.
Cameos of fuel economies of gut, liver, muscle, adipose tissue, brain. Uptake of glucose and its conversion to fuel stores.
Formation of acetyl-CoA from pyruvate. Biosynthesis of fatty acids from acetyl-CoA. Biosynthesis of triacylglycerols (‘fat’).
Digestion of dietary fat: formation and fate of chylomicrons.
Role of other lipoproteins in transferring triacylglycerol from liver to adipose tissue.
The fuelling of muscle contraction by carbohydrate and lipids Mobilisation of glycogen: glycogenolysis.
Fates of pyruvate: reduction to lactate (anaerobic) and oxidation to CO2 (aerobic) Mobilisation of triacylglycerol: lipolysis.
Fatty acid transport to muscle and b-oxidation to acetyl-CoA.
Citric acid cycle and oxidation of acetyl-CoA to complete carbohydrate and fat oxidation. Formation and use of ketone bodies.
Control of fuel storage and oxidation
The interplay of insulin and the catabolic hormones glucagon and adrenaline.
Principles of metabolic control.
Control of glycogen synthesis and breakdown. Control of fatty acid and triacylglycerol synthesis.
Interplay of short-term acute control and longer term adaptive control. Control of lipolysis in adipose tissue.
Control of glycolysis and citric acid cycle. Amphibolic role of citric acid cycle.
Fasting and gluconeogenesis; aspects of amino acid metabolism
Fuel needs of brain and how met in fasting by liver making glucose and ketone bodies. Amino acids in gluconeogenesis and ketogenesis.
Control of gluconeogenesis. Ketosis and diabetes.
Overview of metabolic roles of amino acids and of amino acid catabolism. The importance of aminotransferases and glutamate dehydrogenase.
The urea cycle.
Amino acids and the supply of methyl groups and other ‘one-carbon’ fragments for biosynthesis.
Mitochondrial respiration and oxidative phosphorylation ATP couples exergonic catabolism to endergonic anabolism.
How oxidation is coupled to phosphorylation by mitochondria. Overview of the electron-transport chain.
Some comments on individual redox cofactors.
Experimental background to the ordering of the electron-transport chain. Structure and function of the complexes of the electron-transport chain. How the proton motive force drives the ATP synthase to make ATP. How the proton motive force drives transport in and out of mitochondria.
Dr Marc de la Roche: Membrane Dynamics And Cellular Signalling (5)
Protein trafficking, secretion and endocytosis. Secretion and endocytosis.
Importance of protein trafficking for maintenance and synthesis of intracellular structures. The diabetes context: insulin synthesis and secretion.
Structure of the endoplasmic reticulum, Golgi apparatus and plasma membrane, emphasising their dynamic nature and interrelationship.
Secretion Concept of targeting sequences. Consideration of organelle-specific targeting, protein processing, role of cytoskeleton and motor proteins. Outline of molecular events in secretion.
Endocytosis Pinocytosis and endocytosis in coated pits leading to lysosomes or recycling to plasma membrane. Example of LDL receptors.
Recognition of water-soluble hormones by surface receptors generates a signal inside the cell. The lectures will give an understanding of the key elements of the nature of some of the signals, how they are generated and removed, and how the cell interprets them as a part of its function.
The three basic types of receptor, how they work and why: ligand-gated ion channels, G- protein coupled (7 transmembrane domain), and tyrosine kinase.
The role of trimeric G-proteins in signal transduction, illustrated by control of adenylyl cyclase activity to produce the 2nd messenger cyclic AMP. Actions of cyclic AMP to illustrate protein phosphorylation as a transducing mechanism.
Simple introduction to cyclic GMP and nitric oxide.
Hormonal activation of phosphoinositide hydrolysis and elevation of Ca2+ concentration by inositol trisphosphate.
Action of diacylglycerol to activate protein kinase C.
Phosphatidylinositol 3,4,5-trisphosphate as another lipid second messenger. A brief outline of Ca2+ regulation and its importance as a 2nd messenger.
The operation of tyrosine kinase receptors, illustrated by the (typical) PDGF receptor and the insulin receptor.
Receptor families and the concept of more complex signal transduction cascades involving protein kinases. A complex signal transduction cascade exemplified by the pathway from the insulin receptor to the stimulation of glycogen synthesis.
Dr H R Mott: Molecular Recognition & Drug Design (2)
The aim of these lectures is to understand how molecules interact with one another within the cell. We will consider the basic principles of molecular recognition, focusing on examples from growth factor response pathways. We will then go on to see how knowledge of protein structure and function helps to develop inhibitors that act as drug molecules
Principles of molecular recognition
How the structure of a protein allows it to perform molecular recognition. Bond formation in recognition.
Conformational changes and reversible covalent modification.
Protein-protein and protein-DNA recognition in growth factor response pathways Measuring binding affinities and finding new interactions
Principles of drug design
Design of enzyme inhibitors as drug molecules.
How monoclonal antibodies are produced experimentally. Use of monoclonal antibodies in cancer therapy.
Dr G Yeo: Epilogue (1)
I will use the opportunity to tie together the information covered in the PBL, and will discuss the obesity epidemic: a major threat to public health.
We also have a brief look at leptin and mechanisms regulating appetite and energy expenditure.
The Genome in Health and Disease
Dr T Littlewood. Prologue: Cancer As A Molecular Disease (1)
The lectures provide a general introduction to cancer and the molecules that are involved.
Cancer epidemiology and tumour development
Changes in the incidence of cancer and mortality in the UK and worldwide The causes of cancer
Cancers occur in many distinct forms but are characterised by common features - the hallmarks of cancer
The process of tumour development: vascularisation, invasion and metastasis. The molecular biology of cancer
The relevance of DNA repair mechanisms in cancer
Cancer is primarily a genetic disease. There will an introduction to the classes of genes that promote cancer (oncogenes) and those that are involved in suppressing tumour development (tumour suppressors). A small number of examples will be discussed to illustrate the common principles of their molecular functions.
Dr L. Pellegrini: Organisation, Replication And Repair Of The Genome (5)
Organisation of DNA in the genome DNA is the genetic material.
Chemistry and structure of the DNA double helix. Dimensions and scale of the DNA double helix.
How do you fit 2 metres of DNA into a 10 micron diameter nucleus? Different levels of compaction.
Nucleosomes, nuclear scaffold, chromosomes.
How DNA is replicated
The double helix as a template. Semiconservative replication.
DNA polymerases, requirement for substrates, primers and template. Ensuring accuracy - proof reading.
Discontinuous replication and Okazaki fragments. Origins of replication - the replication fork.
How genomes are replicated.
The problem of linear chromosomes and the solution – telomeres. Centromeres.
Sequencing DNA – classical methods and massively parallel sequencing. Polymerase chain reaction.
Information content of DNA What is a gene?
What is gene expression – cDNA libraries and microarrays?
The human and other genome projects – genomic libraries, sequencing and sequence assembly.
How many genes make a human? Differing sizes of genomes.
Not all DNA encodes genes.
Repetitive DNA, microsatellites, hypervariability and fingerprints. Mobile genetic elements.
Change and constancy of DNA DNA modifications and epigenetics.
Mutations and how they arise. DNA damage and its consequences. Mechanisms of DNA repair.
DNA repair and cancer.
How DNA rearrangements can be a good thing.
Dr Miska: Transcription, Translation And Control (5)
Transcription in prokaryotes and its control Course overview – The Central Dogma
What is a gene? What is mRNA?
Basic mechanism of RNA synthesis (transcription) Regulation of transcription
The lac repressor and the catabolite activator protein (CAP) Antibiotics that inhibit prokaryote transcription
Transcription in eukaryotes and its control RNA Polymerases
Eukaryotic promoters and upstream regulatory elements Regulation of transcription
Roles of chromatin
Enhancers and response elements
Tissue-specific and developmentally regulated transcription factors Transcription factors and cancer – cFos/c-Jun, p53
Pre-mRNA processing - from pre-RNA to mature mRNA ‘Polishing’ pre-mRNA
Termination and polyadenylation RNA splicing
Anomalous splicing and cancer – Wilms tumour Making cDNA and genomic libraries
Translation - Protein synthesis Control of mRNA stability
tRNA structure and charging with amino acids Ribosomes and polysomes: structure and function Initiation of translation
Translation continued – Elongation, termination, degradation Elongation
Control and termination of translation
Antibiotics that target the translational machinery
Protein degradation – the lysosome and the proteasome, ubiquitin. Gene expression studies, arrays and cancer
MicroRNA, siRNA and RNAi.
Professor C Watson: Control Of Proliferation And Death In Cancer Cells (3)
Lectures 1 and 2
The phases of the cell cycle and its regulation
Why do we need to understand cell proliferation and cell death?
Phases of the cell cycle: two gap phases (G1 and G2) a DNA replication phase (S) and a cell division phase mitosis (M). Non-dividing cells (Go).
Regulation of the cell cycle: Cyclins and cyclin-dependent kinases (CDKs) regulate the
transition from one phase to the next.
CDKs are constitutively expressed whereas cyclins are expressed at specific phases of the cell cycle
Cyclin D and CDK4: G1
Cyclin E and CDK2: preparing for S phase Cyclin B and CDK1: the G2-M transition. Regulation of CDK activity
The licensing of DNA replication Re-replication block
Two types of cell division: mitosis and meiosis Stages of mitosis
Spindle assembly checkpoint Chromosome separation Cytokinesis
Aberrant cell division can lead to cancer
Cell death in normal and cancer cells
Two main types of cell death: programmed cell death and necrosis Programmed cell death: apoptosis
Basic mechanisms of apoptosis Executioner caspases and their substrates. The Bcl2 family
The intrinsic and extrinsic pathways
Cancer cells can become resistant to apoptosis Cancer drugs that target cell death pathways
Prof A Ferguson-Smith – Introduction to Medical and Veterinary Genetics
The aim of these lectures is to introduce you to the importance of genetics in human and animal health and to focus on many of the basic principles and concepts which form the foundation for understanding genetics in the clinic and in biomedical research today.
Introduction and foundations (Feb 11th 2016) Introduction to the course
Karyotypes and the architecture of chromosomes Pedigrees and kinship
Mendel’s Laws and some exceptions Meiosis and crossing over
Disease mapping and inheritance (Feb 22nd 2016) Genetic linkage
Recombination frequency and linkage maps Mapping traits, genes and diseases
Single gene disorders Exome sequencing
Autosomal dominant diseases Autosomal recessive diseases
Chromosome aberrations, mechanisms and diagnosis (Feb 23rd 2016) Numerical and structural aberrations
Copy number variation
Diagnosis of chromosomal aberrations Chromosomal abnormalities in disease
Sex and sex chromosomes (Feb 25th 2016) Thomas Hunt Morgan and the white gene
Sex chromosome abnormalities Sex linked disorders
Sex determination and the Y
X inactivation and introduction to epigenetics
Epigenetics, Environment and Disease (Feb 29th 2016)
Genomic imprinting, parental origin effects and imprinted disorders – examples in human and domesticated animals
Epigenetic modifications to DNA and chromatin and their function
Gene-environment interactions and disease – genetic and non-genetic inheritance
Other genetic diseases and mechanisms (Mar 1st 2016)
Twin studies – monozygotic and dizygotic; concordance and discordance Mitochondrial disease and embryological manipulation
Trinucleotide repeat expansion diseases - three different examples acting at different levels providing examples of
Behaviour and analysis of genes and variants in populations (Mar 2nd 2016) Hardy-Weinberg equilibrium
Calculation of allele-frequencies in populations Founder effects and bottlenecks
Sickle cell anemia, malaria and balancing selection Genetic variants in populations
Genetic selection and livestock breeding
Genetics revision lecture – May 3rd 2016 - see Easter term
Dr T Littlewood. Epilogue: Cancer As A Molecular Disease (1)
Cancer genes: oncogenes and tumour suppressor genes
What are oncogenes and tumour suppressor genes and where do they operate in biological processes?
Oncogenes –discovery, mechanisms and consequences of “activation” Oncogene cooperation in tumourigenesis
Tumour suppressor genes – their discovery and the consequences of loss of function The molecular basis of the inheritance of genetic predisposition to cancer.
Translating biochemistry and genetics to the clinic
Dr Alan Wright: Imaging Biology in the Cancer Patient (2)
Our growing understanding of the molecular basis of cancer is allowing the design of new clinical imaging methods that provide early disease detection, that give prognostic information and that can detect early treatment response to guide therapy in individual patients. These lectures will outline the physical principles of these methods and show how they can be used to interrogate specific aspects of tumour cell biology in the cancer patient.
Parallel lecture (1) –details to be given later in the year Professor N. Wareham: Nutrition and Preventive Medicine
Dr P. Watson: Clinical Aspects of Energy Metabolism in Small Animals
Professor A Venkitaraman: Cancer Therapy (1)
This lecture will draw together information from previous lectures to illustrate how fundamental understanding of the biological basis of cancer is transforming approaches to therapy.
- Cancer pathogenesis and its underlying mechanisms
- Conceptual features and modalities for cancer therapy
- Challenges to the development of new therapies
- Case studies:
– Tackling oncogene addiction
– Unleashing the immune response
– Synthetic lethality: hope or hype?
Professor A Ferguson-Smith: Genetics revision session and preparation for exams (1)
Revision session and preparation for exams – it’s all yours.
The purpose of this final lecture is to review specific topics that you will choose from the previous genetics lectures, in preparation for the examination. During the Lent term and Easter break, students are encouraged to contact the lecturer if there is a specific area that they would like to see covered in this session.