Cell response to injury - Endogenous causes 2023-24.pptx

BIS5015-B: Pathology Cell Response to Injury: Endogenous causes Dr Sobia Kauser 2023-24  Learning Outcomes 1) Interaction between genes and environment in disease aetiology - Environmental factors acting via disease - Genetic composition influencing...

BIS5015-B: Pathology Cell Response to Injury: Endogenous causes Dr Sobia Kauser 2023-24  Learning Outcomes 1) Interaction between genes and environment in disease aetiology - Environmental factors acting via disease - Genetic composition influencing environmental reactivity 2) Genetic disorders - Major chromosomal abnormalities - Minor chromosomal abnormalities 3) Phenocopy Introduction: Classifications of cell injury Physical Genetic Chemical Endogeno Exogeno Microbiological us Origin us Origin Immunological Ageing Nutritional NATURE NURTURE (environment) Introduction: Endogenous Injury Gene or chromosomal defect Genetic Endogeno Primarily genetic BUT us Origin can still be influenced by exogenous factor Ageing e.g. Phenylketonuria NATURE (PKU) and diet (more on this later…)  Introduction: Exogenous Injury External e.g. Ebola Primarily environmental Physical BUT may be a genetic Chemical influence on persons’ resistance Exogeno Microbiological us Origin Immunological Environment may act Nutritional via genes: NURTURE (environment) Radiation Somatic Cancer mutation  Introduction: Classifications of cell injury Physical Genetic Chemical Endogeno Exogeno Microbiological us Origin us Origin Immunological Ageing Nutritional NATURE NURTURE (environment) Cause of disease is MULTIFACTORIAL and often includes both ENDOGENOUS and EXOGENOUS injury  Introduction: Classifications of cell injury Physical Genetic Chemical Endogeno Exogeno Microbiological us Origin us Origin Immunological Ageing Nutritional NATURE NURTURE (environment) Cause of disease is MULTIFACTORIAL and often includes both ENDOGENOUS and EXOGENOUS injury  CRI – Endogenous causes Genes How can genes influence how a person responds to the environment?  Genes and the environment - Schizophrenia Breakdown in relationship between thought, emotion and behaviour  faulty perception about reality 20-70% in monozygotic www.webmd.com twins Genetic role DISC1, dysbindin, neuregulin, G72 amongst others BUT environmental stimuli Incidence = 1% are important too Rubella, grief, CNS www.schizophrenia.com  Genes and the environment - Neoplasia New and abnormal growth of tissue – rapid division of cells that have acquired a mutation Familial adenomatous polyposis of the colon Benign and cancerous polyps in the colon and rectum Autosomal dominant (APC) or autosomal recessive (MUTYH) Diet and lifestyle can influence the disease. http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/small_large_intestine/familial_adenomatous_polyp  Genes and the environment - Breast Cancer Common cancers have strong environmental influence BUT genetic influence also apparent e.g. Breast cancer ATM Lifetime risk: /ATR 1:8 (women), 1:868 (men) BRCA1 5-10% inherited type DNA dama BRCA1 and BRCA2 ge BReast CAncer gene Cell repair cycle Breast and / or ovarian arrest cancer in relatives http://www.cancerresearchuk.org/about-cancer/type/breast-can  Genes and the environment - Major Histocompatibility Complex MHC MHC = set of genes encoding cell surface molecules that determine histocompatibility Present pathogen peptide Unknow Multi- fragments for T cells n factori aetiolog al Recognition of self y HLA diseas HLA genes highly es polymorphic (~1500 Famili Potential alleles) al ly viral Auto- immune Graft rejection – donor reactions HLA on cell surface elicits immune response in  Genes and the environment - MHC – Ankylosing Spondilitis Spinal arthritis primarily affecting young males, causing ankylosis of vertebral and sacroiliac joints Arthritic fusion of sacroiliac and vertebral joints Ossification of spinal ligaments leading to spinal rigidity HLA-B27 variant 95% of AS patients 9% of general population http://nass.co.uk/  Genes and the environment - MHC – Multiple Sclerosis Progressive disease of the spinal cord and brain Patches of demyelination Loss of nerve www.webmd.com conductance and muscle control paralysis and death HLA-DW2 variant 5x more likely to develop MS Viruses, location, vitamins, smoking www.mssociety.org.uk A Quick Question….. Are there any other diseases that have both genetic and  A Quick Question….. Most diseases / disorders have both a genetic and environmental component – here are last years students thoughts… Addison Crohn’s ’s Disease / Melanin Disease Coeliac conc. Depressi Disease and on skin Psoriasi cancer Hypertensi s, on Eczema Thrombos Allergie Parkinso is s n’s Diabete Disease s  Learning Outcomes 1) Interaction between genes and environment in disease aetiology - Environmental factors acting via disease - Genetic composition influencing environmental reactivity 2) Genetic disorders - Major chromosomal abnormalities - Minor chromosomal abnormalities 3) Phenocopy  Genetic Disorders Visible changes in chromosomes Inherited Somatic Major Single cells Minor All cells Clonal NATURE NURTURE (environment) Invisible – single gene Major Chromosomal Abnormalities Visible changes in chromosomes Inherited Somatic Major Single cells Minor All cells Clonal NATURE NURTURE (environment) Invisible – single gene  Major Chromosomal Abnormalities - Turner Syndrome 45 chromosomes - loss of an X chromosome 1:2000 female births Random genetic event occurring at conception Short stature, Linda Hunt underdeveloped ovaries NCIS: Incurable but treatment LA with growth hormone, HRT, IVF http://tss.org.uk/  Major Chromosomal Abnormalities - Down’s Syndrome 47 chromosomes - trisomy of chromosome 21 1:1000 births Random genetic event occurring at conception Child of Down’s parent = 1:2 Liam Reduced muscle tone, Bairst facial characteristics, ow learning problems Corrie Incurable, treatment based around social care www.downs-syndrome.org.uk Major Chromosomal Abnormalities - Neoplastic Cells Rapid division of cells that have acquired a mutation, often have increased no. chromosomes Multiple Basal Cell myelom Carcinoma a Blue = nucleus BM Yellow = chr. 1 cancer  A Quick Question….. What’s the name of the assay? Karyotypin Minor Chromosomal Abnormalities Visible changes in chromosomes Inherited Somatic Major Single cells Minor All cells Clonal NATURE NURTURE (environment) Invisible – single gene Minor Chromosomal Abnormalities Generally rare Minor If common: Confers selective Deleteriou advantage s to life = Most likely Invisible – not passed heterozygous single gene on  Minor Chromosomal Abnormalities - Sickle Cell Anaemia Hereditary anaemia caused by mutation in haemoglobin. Red blood cells become crescent shaped in low O2 Single base substitution in haemoglobin beta chain 1:2400 births Rare recessive – need two copies One copy = sickle cell trait http://sicklecellsociety.org  Minor Chromosomal Abnormalities - Sickle Cell Anaemia Hereditary anaemia caused by mutation in haemoglobin. Red blood cells become crescent shaped in low O2 African – Caribbean population = 1:10 sickle cell trait Protective against malaria – mechanisms still being identified Shape CO release microRNAs http://sicklecellsociety.org Minor Chromosomal Abnormalities - Phenylketonuria (PKU) Inability to metabolise Phenylalanine (Phe) Amino acid synthesi Tyrosine Phe Neurotransmitters Dopamine, adrenalin Essenti al Skin biology amino Melanin acid  Minor Chromosomal Abnormalities - Phenylketonuria (PKU) PKU Phe in blood Phenylalanine and CSF Hydroxylase  15- 100x Myelinatio Rare recessive n in NURTURE developing NATURE (environment) brain Severe mental retardati Minor Chromosomal Abnormalities - Phenylketonuria (PKU) Treatment? Phenocopy Restricted diet Mother Child Guthrie test at PKU no PKU birth Phe in mother’s Mental cord retardati blood on Minor Chromosomal Abnormalities - Phenylketonuria (PKU) Treatment? Phenocopy Restricted diet Mother Child Guthrie test at PKU no PKU birth Phe in mother’s Mental cord retardati blood on  Learning Outcomes 1) Interaction between genes and environment in disease aetiology - Environmental factors acting via disease - Genetic composition influencing environmental reactivity 2) Genetic disorders - Major chromosomal abnormalities - Minor chromosomal abnormalities 3) Phenocopy  Introduction: Classifications of cell injury Physical Genetic Chemical Endogeno Exogeno Microbiological us Origin us Origin Immunological Ageing Nutritional NATURE NURTURE (environment) Cause of disease is MULTIFACTORIAL and often includes both ENDOGENOUS and EXOGENOUS injury  CRI – Endogenous causes Ageing How does age damage people at a cellular level?  Learning Outcomes 1) Features of ageing 2) Telomeres 3) Senescence - Hayflick Limit - Features of senescence 4) Premature ageing 5) Factors affecting ageing  Ageing All good things come to an end…. All biological organisms will die 1 week 2 years 6 months 13 years 19 years 82 years 1 day 182 years  Signs of Ageing “I just can’t see / hear / run as well as I used to…” Greying and/or Muscle loss of hair weakness / atrophy Skin thinning A Quick Question….. What other signs of ageing can you think of?  A Quick Question….. Here are last years students thoughts…. Cataracts Confusion, forgetfulnes Shrinking s Stiffness Infertility Prone Loss of to bone infectio Hair density n Loss of growing sensory from nose / function ears (hearing,  Disorders linked to Ageing 1911 = 5% UK aged >65 years 2011 = 16% Social and economic impact - NHS T2DM Cancer Alzheimer’s Disease / Cardiovascular Glaucom dementia Disease  Learning Outcomes 1) Features of ageing 2) Telomeres 3) Senescence - Hayflick Limit - Features of senescence 4) Premature ageing 5) Factors affecting ageing  Telomeres Long stretches of DNA that cap the end of chromosomes Part of telomere lost at each cell division protects coding DNA from decay Telomere shortening gradually leads to ageing and loss of ability to divide  Telomerase Reverse transcriptase enzyme that elongates telomeres Normal somatic cells: Cancer and stem cells:  Senescence – Hayflick Limit Number of times a cell will divide until cell division stops Population Doublings Foetus ~50x 40 years ~40x 80 years ~30x Proliferation slows down Cell cycle halts in G0 Temporary = quiescence Permanent =  Senescence Cells stop dividing and undergo phenotypic alteration Telome DNA re damage / attritio ROS Proliferation n Lamin  B1 Angiogenesis Cell Senescenc e Neighbouri Wound healing ng cells Inflammation Senescence- Cell cycle associated withdraw secretory al phenotype JM van Deu The Role of Senescent Cells in Ageing Nature 2014;509:439  A Quick Question….. Is senescence good or bad in the following scenarios? Proliferation Angiogenesis Wound healing  A Quick Question….. Angiogenesis is the formation of new blood vessels. Endothelial Senescence would counteract cells need to be active to start the proliferation. This is a good process so senescence here would thing in a cancer (it would help to be bad. However, once the new stop the cancer from spreading) blood vessel has formed the cells but would be a bad if you needed no longer need to proliferate and proliferation e.g. during so senescence would be more development, healing, etc. appropriate. Angiogenesis in cancer or in some conditions in the retina can propagate disease, Wound healing needs actively andInflammation so senescence is in anthese important cases proliferating and migrating cells biological process would be goodbut can be to proceed, so senescence at the detrimental if it lasts longer than beginning of wound healing would it should or is more severe than it not be good. However, it may should be. Senescence can play a role once the wound has increase the inflammatory healed and the cells no longer response by being a source of need to be active. cytokines (senescence-associated  Senescence Why do we get more senescent cells with age? Accumulation in aged Damagi Cell humans, primates and ng clearan rodents stimuli ce Accumulation in age- related diseases – e.g. cardiovascular disease, Alzheimer’s Disease JM van Deu The Role of Senescent Cells in Ageing Nature 2014;509:439  Senescence Why do we get more senescent cells with age? Damagi ng Accumulation in aged stimuli Damagi Cell humans, primates and ng clearan rodents stimuli Cell ce clearan ce Accumulation in age- related diseases – e.g. cardiovascular disease, Alzheimer’s Disease JM van Deu The Role of Senescent Cells in Ageing Nature 2014;509:439  Learning Outcomes 1) Features of ageing 2) Telomeres 3) Senescence - Hayflick Limit - Features of senescence 4) Premature ageing 5) Factors affecting ageing  Premature Ageing - Cardiovascular Disease Premature ageing – Abdominal Aortic Aneurysm Dilation of the aorta Rupture = 90% mortality Inflammation Aorta Loss of smooth muscle cells SV AAA AA A K Riches et al. Journal of Translational Medicine 2013; 11: K Riches et al. Journal of Vascular Research 2018;55  Premature Ageing - Progeria Hutchinson-Gilford Progeria Syndrome = mutation in Lamin A, nuclei become unstable premature ageing 1:4-8,000,000 Autosomal dominant, random genetic event Rapid ageing from 18-24 Sam Berns, age months 17 Children die aged ~14 from cardiovascular disease www.progeriaresearch.org Premature Ageing – Werner Syndrome Rare progressive disorder characterised by premature ageing 1:20,000,000 J Lucentini. The Scientist 2005. Autosomal recessive mutation in WRN DNA helicase gene - DNA repair / division Growth halted at puberty, visible ageing ~25 years Life expectancy 40-50 years, mortality from cardiovascular disease https://rarediseases.org/rare-diseases/werner-syndrom  Factors affecting ageing Oxidativ e stress Telome re DNA damage / length repair mechanisms “5-a-day” Anti- Telomerase activity oxidants Dietary (caloric) restriction: Extends lifespan Delays onset of age- A Metaxakis et al. PLoS ONE 2013; 8(9):e746  Learning Outcomes 1) Features of ageing 2) Telomeres 3) Senescence - Hayflick Limit - Features of senescence 4) Premature ageing 5) Factors affecting ageing