Outline of the MIMS lecture course
Important note. This information 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 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 Monie BIOLOGICAL MACROMOLECULES, PROTEIN STRUCTURE AND ENZYME CATALYSIS (6)
After an introduction to macromolecules, the lectures concern understanding of the structure of proteins and how structure influences function. We will focus particularly on enzymes, seeing how they catalyse reactions and how this activity is controlled. We will study examples of the structures of medically relevant enzymes and see how knowledge of their structure and function helps to understand disease and develop inhibitors that act as drug molecules.
Lecture 1. Introduction of macromolecules.
The major macromolecules in the cell will be introduced. We will learn about the monomeric building blocks (monosaccharides, nucleotides, amino acids) and the functionally critical polymers they form (polysaccharides, nucleic acids, proteins).
Lectures 2-3. Structure and function
The principles and different levels (primary, secondary, tertiary, quaternary) of protein structure will be introduced. We will learn how the structure of a protein is determined by its amino acid sequence and how amino acids interact with one another to form the structural elements that make up the final protein structure. The role and use of prosthetic groups and co-factors will be introduced as will methods of studying protein structure. Protein function will be introduced through specific case studies, such as HIV protease and haemoglobin.
Lectures 4-6. Enzyme function and control
In these lectures we will focus on proteins as enzymes (biological catalysts). We will investigate the thermodynamic necessity for enzymes; the kinetics of enzyme activity (Michaelis-Menten); and the classification and characterisation of enzyme function. In addition, the mechanisms by which enzymes catalyse biological reactions will be explored, as will the various ways in which enzymes can be controlled. The design of specific enzymes inhibitors as therapeutics will be discussed.
Dr. R. W. Broadhurst, Prof. P. Leadlay. BIOENERGETICS AND METABOLISM (8)
- 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.
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 -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.
Dr Pereira – Nutrition (2)
Lecture 1. Vitamins and trace elements.
Key concepts in micronutrient nutrition
Vitamins and trace elements, their biological roles and nutritional requirements. Micronutrient deprivation and deficiencies.
Lecture 2. Oxidative stress and phytochemicals.
Oxidative stress and antioxidants.
Risk/benefit balance of micronutrient supplementation.
Prof. Taylor MEMBRANE DYNAMICS AND CELLULAR SIGNALLING (5)
These lectures are being revised extensively. While the overall topics covered will be as below the details and organisation will be different. An updated outline will be posted later in term.
Lecture 1. 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.
Lectures 2-5. Hormonal signalling
- 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 Yeo EPILOGUE (1)
The aim of the Epilogue is to draw together aspects of the term's lectures, as they relate to insulin structure and function and the causes of diabetes.
- Mutations in glucokinase or the insulin receptor as rare causes of diabetes.
- Central role of protein phosphorylation (tyrosine and serine) as a regulatory mechanism.
- Glucose transporter isoforms: an example of horses for courses.
- Causes of type 2 diabetes revisited: defective genes or foetal programming?
- Prospects for novel diabetes therapies: where should we be looking?
- Understanding the obesity epidemic: a major threat to public health.
- A brief look at leptin and mechanisms regulating appetite and energy expenditure.
Lent Term. Macromolecules in Health and Disease
Dr T Littlewood. PROLOGUE: CANCER AS A MOLECULAR DISEASE (2)
The lectures provide a general introduction to cancer that requires minimal background knowledge.
Lecture 1. Cancer incidence and development
- Cancers occur in many distinct forms but are characterised by common features.
- Major human cancers: Incidence and mortality in the U.K. and worldwide.
- Cancer defined.
- The process of tumour development: vascularisation: metastasis.
- Cancer primarily a disease of (somatic cell) genetic mutation.
Lecture 2. Cancer
- Introduction to oncogenes: mechanisms of activation.
- Tumour suppressor genes.
- Inheritance of genetic predisposition to cancer.
- Micro RNAs: oncogenes and tumour suppressors.
Dr L. Pellegrini ORGANISATION, REPLICATION AND REPAIR OF THE GENOME(5)
Lecture 1. 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.
Lecture 2. 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.
- Sequencing DNA – classical methods and massively parallel sequencing.
- Polymerase chain reaction.
Lectures 3-4. 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.
- Junk DNA?
- Repetitive DNA, microsatellites, hypervariability and fingerprints.
- Mobile genetic elements.
Lecture 5. 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)
Lecture 1 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
Lecture 2 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
Lecture 3 Pre-mRNA processing - from pre-RNA to mature mRNA
- ‘Polishing’ pre-mRNA
- 5’ Capping
- Termination and polyadenylation
- RNA splicing
- Alternative splicing
- Anomalous splicing and cancer – Wilms tumour
- Making cDNA and genomic libraries
Lecture 4: Translation - Protein synthesis
- Control of mRNA stability
- Genetic code
- tRNA structure and charging with amino acids
- Ribosomes and polysomes: structure and function
- Initiation of translation
Lecture 5: Translation continued – Elongation, termination, degradation
- 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
Dr Laman and Dr D’Avino CONTROL OF PROLIFERATION AND DEATH IN CANCER CELLS (3)
Lecture 1. The clockwork of the cell cycle
- Phases of the cell cycle: G1, S, G2, and Go
- Cyclins and cyclin-dependent kinases regulate cycle phase-transition.
- Cyclin B and cdk1 (cdc2): the G2-M transition.
- Substrates of cdk1 in cytoskeleton, nuclear membrane and chromosomes.
- APC/C (the anaphase-promoting complex): servant and master of cyclin B.
- Events driven by other cyclin-dependent kinases.
- Cyclin D and Rb (the retinoblastoma protein).
- E2F-1 and G1 progression.
- The cyclin D/Rb/E2F pathway and carcinogenesis: action on cell proliferation and death.
Lecture 2. Controls of progression into and through the cell cycle
- Extracellular signals that activate cell cycle entry: growth factors, tyrosine kinases, ras, the MAP kinase and PI3-kinase pathways.
- The pre-replicative protein complex: constraints on inappropriate initiation of DNA replication.
- Checkpoints at G1-S transition, G2-M transition and during spindle formation.
- Activation of checkpoints: cytokines (e.g. TGF), injury, hypoxia.
- p53 - guardian of the genome.
- Cell cycle controls, checkpoints and carcinogenesis: mutations of p53, ras, MAP kinase pathway oncogenes.
Lecture 3. When checkpoints fail: apoptosis and carcinogenesis
- Basic mechanisms of apoptosis.
- Caspases and their substrates.
- Signalling to the caspase cascade: mitochondrial and membrane receptor pathways.
- The bcl-2 family.
- Phenotype of cancer: the undead cell.
- Many mutations are required for carcinogenesis.
- Virus proteins, carcinogen-induced mutations, inheritance in cancer susceptibility.
- Overall summary.
Dr Mott MOLECULAR RECOGNITION (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 and antibody mediated recognition.
Lecture 1. 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 recognition of specific DNA sequences.
- Illustration of these principles by considering growth factor response pathways.
Lecture 2. Antibodies
- Antibody structure and function.
- How monoclonal antibodies are produced experimentally.
- Use of monoclonal antibodies in cancer therapy.
Dr Crowther GENETICS in human and animal medicine (5)
Lecture 1. Tracing genes and chromosomes
- Problems of human genetics -small family sizes, long generation times.
- Tracing the inheritance of single gene traits through pedigrees.
- Autosomal and sex-linked inheritance , dominant and recessive alleles.
- X-inactivation in female mammals.
- Mitochondrial inheritance.
Lecture 2. Locating genes to chromosomes
- Meiosis and gamete formation.
- Independent segregation of genes on different chromosomes.
- Linkage of genes on the same chromosome.
Lecture 3 Building chromosome “maps”
- Genetic markers -tracing genes by changes to DNA or protein sequence.
- Protein markers(blood groups, haemoglobins), and DNA based markers (microsatellites and SNPs).
- Detecting linkage in pedigrees- The importance of linkage studies in human genetics.
- Finding and studying the genes which contribute to disease.
Lecture 4. How genetic variation and environment determine phenotype
- Animal coat colour genes- combinations of alleles in several different genes give different phenotypes.
- Multifactorial inheritance, where several genes co-operate to produce a phenotype.
- The multifactorial basis of common mid-life diseases.
- Why twins and affected sibs are important for these studies.
Lecture 5. Genes in populations
- Relating phenotypes to allele frequencies- the Hardy –Weinberg equation.
- Selection in action- Malaria and sickle cell haemoglobin.
- Host pathogen interactions in bacterial and viral disease.
- Evolution of multiple drug resistance.
Prof A Venkitaraman MESOLOGUE. CANCER THERAPY (1)
The lecture draws together the cancer theme so far developed, including therapeutic approaches, and looks forward to the final group of lectures on genetics.
(That’s why we have called it a mesologue, rather than an epilogue - in case you wondered.)
Easter Term. Macromolecules in Health and Disease, continued
Dr Sargent. GENETICS in human and animal medicine, continued (4)
Lectures 6-9 Introduction to the study and understanding of genetic disease
Lecture 6: Understanding the genome at the chromosomal level
- Speciation and chromosomal number
- Impacts on fertility
- Using karyotypic information to identify disease-causing genes.
- Sex chromosome and autosomal anomalies.
- FISH as a technique to identify changes in the karyotype
Lectures 7 and 8: Understanding the genome at the DNA sequence level
- Variation in the genome defines our differences
- How the genome's information is used depends upon developmental stage of the organism and which tissue we investigate
- Generating a reference genome; genome sequencing strategies, genomic libraries, cDNA libraries.
- Using the reference genome to understand the molecular basis of disease
- The impact of the genome projects and combining information from linkage studies and sequencing studies
- Analysing the candidate genes.
- Types of disease-causing DNA mutation.
- Methods of mutation screening, including DNA sequencing, PCR, Southern blotting, and methods for assessing copy number loss and gain.
Lecture 9: Understanding the impact of genetic mutation
- Sequence conservation across species allows us to use model systems to understand disease processes
- Using our knowledge in practice
- Where might genomics take us in the future?