June

 27,  2016   Dr.  Gonzalo  B.  Roman  │  The  Cell  as  a  Unit  of  Health  &  Diseases  │  Pathology  
 
• Pathos  –  “suffering”   • NON-­‐CODING  REGIONS  
• Pathology  –  Study  of  Suffering  /  Diseases   § “architectural  planning”  
• Virchow  –  coined  Cellular  Pathology;  all  diseases   § specifies  specificity    
originate  at  a  “cellular  level”    
  • Gene  interaction  dictates  SPECIFIC  TRAITS  
AP  walk  –  slang  for  a  slouched  walk  for  a  person  with   (PHENOTYPE)  
appendicitis   a) Promoter,  enhancer  regions  
  (binding  sites  for  transcription  
I.  THE  GENOME   factors)  
• The  gene  complement  of  an  organism  (genes  specific   b) Binding  sites  for  factors  that  
for  a  physical  trait  or  disease)   organize  &  maintain  higher  order  
• Genomic  mapping     chromatin  structures  
o assignment  of  genes  to  specific   c) Non-­‐regulatory  RNAs  (miRNA  &  
chromosomes   lncRNA)  
• Human  Genome  Project   d) Transposons  (jumping  genes)  
o International  project  to  identify  &  localize   e) Telomeres  (chromosome  ends)  &  
the  over  30,000  estimated  genes  in  the   centromeres  (tethers)  
human  genome    
o The  human  genome  contains  roughly  3.2   • Humans  &  chimpanzees  share  99%  of  their  DNA  
Billion  DNA  base  pairs  [on  1  small  nucleus]   sequence  
o Within  the  genome,  there  are  about  20,000   • Any  2  individuals  share  >99.5%  of  their  DNA  
protein-­‐coding  genes,  comprising  only  about   sequences  
1.5%  of  the  genome.   o The  remaining  0.5%  represents  person-­‐to-­‐
  person  variation,  differential  susceptibility  to  
  In  other  words:   diseases,  and  in  response  to  environmental  
  Human  Genome  (3.2B  DNA  base  pairs),  1.5%  of  that  human   agents  &  drugs.  
genome  is  comprised  of  20,000  protein-­‐coding  genes.   o 0.5%  represents  about  15million  base  pairs  
 
 
  The  protein-­‐coding  genes  will  produce  enzymes,  structural    
  components,  &  signaling  molecules   • DNA  Variation  (0.5%)  Most  Common  
  a. Single  Nucleotide  Polymorphism  (SNP)  
o Interaction  of  several  genes  is  required  to   § 6  Million  known  SNPs  
manifest  a  certain  trait,  provided  with  the   § Variants  at  a  single  nucleotide  
appropriate  environment.   positions  
o DNA  Base  Pairs:  A-­‐T  &  G-­‐C   o Nucleotide  –  3  pairs  
o Any  cell  with  a  NUCLEUS  contains  a  genome     § Biallelic  (only  2  choices  exist  at  a  
§ RBCs  don’t  have  a  nucleus,  so  they  don’t   given  site  within  the  population,  
have  a  genome.   such  as  A  or  T)  
 
§ Occurs  within  exons,  introns,  
  WORMS  
  • Contains  <1,000  cells  with  genomes  of  only  about   intergenic  regions,  &  coding  regions  
  0.1  Billion  DNA   o 1%  occur  at  coding  regions  
  o Also  assembled  using  20,000  genes  that   o Non  coding  regions  are  regulatory  
  produce  proteins  (same  as  humans)   elements  for  gene  expression  
  • What  differs  them  from  humans  lies  in  the  98.5%   § In  other  instances,  SNPs  may  be  
  part  of  the  human  genome  that  DOESN’T  ENCODE   neutral  variant  that  has  no  effect  on  
  PROTEIN  
  gene  function  or  carrier  phenotype.  
o d/t  genomic  blueprints  rather  than  
  construction  materials   § Its  effect  on  disease  susceptibility  is  
    WEAK  –  it  is  useful  as  a  marker.  
o 80%  of  the  human  genome  either:   b. Copy  Number  Variation  (CNV)  
1. Binds  proteins   § Large,  continuous  stretches  of  DNA  
Ø Implying  it  is  involved  in  gene   from  1000  base  pairs  to  millions  of  
regulation   base  pairs  
2. Assigned  some  functional   § Biallelic  
Ø Mostly  related  to  regulation  of   § CNVs  are  responsible  for  between  
gene  expression  (cell-­‐type   5-­‐24  million  base  pairs  of  sequence  
specific  fashion)     difference  in  any  2  individuals  
 

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PROPERTY  OF  AUF  SOM  BATCH  2019  
USE  AT  YOUR  OWN  RISK!   Page  1  
 
 June  27,  2016   Dr.  Gonzalo  B.  Roman  │  The  Cell  as  a  Unit  of  Health  &  Diseases  │  Pathology  
 
§ 50%  of  CNVs  are  gene  coding   II.  CELLULAR  HOUSEKEEPING  
sequences  (determines  phenotype   • Environmental  protection    
diversity  –  RACES)   (plasma  membrane)  
  • Nutrient  acquisition    
• Histone  Organization   (Glucose  -­‐>  oxygen)  
o DNA  is  a  spherical  helix  which  would  around   • Communication    
a  HISTONE   (interleukines)  
o DNA-­‐HISTONE  complex  resembles  a  series  of   • Movement    
beads  (“prayer  beads”  according  to  Dr.  Ric).  This  is   (growth;  skin  -­‐>  basal  cells  -­‐>  
now  called  a  NUCLEOSOME   para/intermediate/surface  -­‐>  cornified  or  
o Nucleosome  with  DNA  linkers  then  form   keratinized/dead  cells)  
CHROMATIN   • Renewal  of  senescent  molecules    
o [DNA  +  HISTONE  =  NUCLEOSOME  -­‐>  CHROMATIN]  
(mitochondria)  by  protein  blocks  
 
o Types  of  Chromatin   • Molecular  catabolism    
a. Heterochromatin   (waste  products  mgmt.)  
• Inactive   • Energy  generation  
• Compact  (wound)    
b. Euchromatin   Proteins    
• Active   o From  Rough  ER  
• Dispersed  (unwound)   o Assembled  at  Golgi  apparatus  (further  refined)  
• Gene  expression    
  a.  Lysosomes  –  (+)  degradative  enzymes  
• Micro  RNA  (miRNA)  &  Long  Noncoding  RNA   b.  Proteasomes,  Peroxisomes  -­‐    specific  degradation  
(lncRNA)   c.  Endosomal  vesicles  –  shuttles  internalized  material  
o Gene  regulation  depends  on  NONCODING   d.  Cytoskeleton  –  for  cell  mov’t,  shape,  &  IC  organization  
RNAs     *Columnar  cells  –  determines  polarity  
o They  are  encoded  by  genes  that  are   e.  Mitochondrion  –  ATP  production  d/t  Oxidative  
TRANSCRIBED  but  not  TRANSLATED   Phosphorylation  
   
1. miRNA   1.  Plasma  Membrane  
o Fluid  ampiphatic  bilayers  of  phospholipids  with:  
• short  RNAs  (22  nucleotides)  
§ Hydrophilic  head  groups  
§ Do  not  encode  proteins  
o Loves  water;  faces  ECM  
§ Modulate  translation  of  target  
§ Hydrophobic  tails  
mRNAs  into  their  corresponding  
o Hates  water;  barrier  for  
proteins  
large/charged  molecules  
§ Functions  in  gene  regulation  by  
*Lipid  layer  –  BARRIER!  
posttranscriptionally  silencing  gene   o (+)  heterogenous  different  phospholipids;  
expression   Asymmetrical  distribution  
2. lncRNA   o Proper  distribution  =  good  health  
• modulates  gene  expression  in  many    
ways:   a.  P.  inositol  –  electrostatic  scaffold  @  inner  leaflet  
o gene  activation   b.  P.  serine  –  inner  -­‐>  outer  =  APOPTOSIS  signal  
o suppression   c.  Glycolipids  &  Sphingomyelin  –  EC  face;  Cell-­‐to-­‐cell  
o increases  chromatin   &  cell-­‐ECM  interactions  
modification    
o (+)  protein  complexes   o Some  components  CONGLOMERATE  /  MOVE  
  TOGETHER  (like  lipids)  -­‐>  “lipid  raft”  
  o Proteins  +  Glycoproteins:  
  § Ion  &  metabolite  transport  
  § Receptors  
  § Ligands  
   
   
   
   

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PROPERTY  OF  AUF  SOM  BATCH  2019  
USE  AT  YOUR  OWN  RISK!   Page  2  
 
 June  27,  2016   Dr.  Gonzalo  B.  Roman  │  The  Cell  as  a  Unit  of  Health  &  Diseases  │  Pathology  
 
2.  Cytoskeleton   • Biosynthetic  Machinery:  Golgi  Apparatus  &  ER  
o Shape,  polarity  (apical/basal  membrane),  relationship   o Production  (ribosomes)  =  Degradation  
of  IC  organelles,  mov’t   (lysosomes)  
   
o Classes:   • ER  –  transmembrane  CHON,  organelle  
a.  Actin  microfilaments   production  
§ 5-­‐9nm  diameter   • Golgi  App  
§ from  G-­‐actin  (globular)  -­‐>  long  polymerize  F-­‐ o (+)cisternae  -­‐>  modifies  CHON  in  a  (cis-­‐
actin   trans  way)  
§ e.g.,  myosin  +  actin  -­‐>  mov’t  d/t  ATP   o increased  in  cells  for  secretions  (GIT,  
hydrolysis  [CONTRACTION]   Pancreas,  ovary,  testis,  thyroid,  PTH  
  organ)  
b.  Intermediate  filaments   • Lysosomes  
§ 10nm  d.   o (+)enzymes  for  denaturation  
§ Lamin  A,  B,  C   o 40  diff.  acid  hydrolases  (even  
§ Vimantin  (mesenchymal,   BACTERIA):  proteases,  nucleases,  
chondro/fibroblasts)   lipases,  glycosidases,  phosphatases,  etc.  
§ Desmin  (muscle  cells)   • Proteases  
§ Neurofilaments  (axons)   o Cytosolic  protein  (even  cell  itself)  -­‐>  d/t  
§ Glial  Fibrillary  Acidic  Protein     severe  infection  
o Identify  tumor  cell  specificity  (bone,   • Mitochondria  
neuron,  etc.)   o Power  plant  (ATP  production  &  storage)  
o Special  stain   o Organic  compounds  -­‐>  energy  for  cell  
§ Cytokeratins   itself  
o 30  distinct  varieties   o (+)  enzymes  for  collecting  food  stuffs  -­‐>  
o epithelial  cells  (squamous  cells)  skin   convert  to  energy  
  o Energy  not  used/stored  is  dissipated  as  
c.  Microtubules   HEAT  to  maintain  constant  body  temp.  
§ 25nm  thick   o Contain  their  own  DNA  &  ribosomes  for  
§ alpha  &  beta  tubulin  non  covalent  polymers   self-­‐replication  
§ moves  vesicles,  organelles,  or  other   § Mitochondrial  DNA  –  13;  for  function;  
molecules  around  cells  along  microtubules   maternal  inheritance  
using  ATP   § Nuclear  DNA  –  for  structure  
   
   
§ Cell-­‐to-­‐cell  Interaction   III.  CELL  DEATH  
o (+)  mechanical  links  from  junctions   • Mitochondria  regulates  balance  of  cell  survival  &  
  death  
a.  Occluding  (tight)   • 2  Major  Pathways:  
§ Blood  brain  barrier  –  prevents  passage    
of  molecules;  increase  dosage  to  allow   1. Necrosis  
diffusion  of  antibiotics   • d/t  EC  injury  (toxins,  ischemia,  trauma)  
b.  Anchoring  (desmosomes)   -­‐>  increased  mitochondrial  permeability  
§ Seen  at  light  microscope   -­‐>  mitochondrial  damage  -­‐>  proton  
§ Squamous  +  squamous   potential  disruption  -­‐>  (-­‐)  ATP  
§ extracellular  bridges   production  -­‐>  cell  death  
c.  Communicating  (gap)     2.  Apoptosis  
§ tissue  pores   • intrinsic  (by  mitochondria)  /  extrinsic  
  stimuli  
   
   
   
   
   
   
   

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PROPERTY  OF  AUF  SOM  BATCH  2019  
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 June  27,  2016   Dr.  Gonzalo  B.  Roman  │  The  Cell  as  a  Unit  of  Health  &  Diseases  │  Pathology  
 
IV.  CELL  ACTIVATION   • Growth  Factors  
EC  signal  –  it  lives  or  dies,  grow  or  regress   o Increased  at  pituitary,  some  are  at  local;  for  
Signals     cell  growth  &  division  
o chemicals  (if  injurious,  there  will  be  enzymes  to   § Promote  entry  of  cell  at  cell  cycle  
increase  protection),  CHONs   § Blocks  cell  cycle,  progression  (for  
o for  adaptive  response  to  various  threats   promoting  replication)  
• local  trauma   § Apoptosis  
o punched  by  Manny  Pacquiao  -­‐>   § Biosynthesis  of  cell  components  
black  eye  (hematoma   (normal  proportion)  
formation)  -­‐>  prevents  spread   o e.g.,  Epidermal  GF,  Hepatocyte  GF,  Platelet  
è ADAPT   GF,  Vascular  GF,  Fibroblast  GF,  Transforming  
• Systemic  infection   GF  –  beta  
o Tonsil  infection  -­‐>  spread  -­‐>    
septicemia    
  VI.  INTERACTION  WITH  ECM  
• Loss  of  communication  -­‐>  unregulated  growth  -­‐>   • Network  of  interstitial  proteins  
CANCER   • For  development,  healing  &  maintaining  tissue  
  architecture  
• Cell  Signaling    
o Differentiates,  proliferates   • ECM  
• d/t  damage  to  neighboring  cells  &   o Mechanical  support  
pathogens   o Scaffolding  for  tissue  renewal  &  
• contact  inhibition  (neighboring  cells)   microenvironment  
• contact  with  ECM   o 2  Forms:  
• secreted  molecules   a. Interstitial  Matrix    
o e.g.,  thyroid  only  responds  to  TSH  d/t   • Type  1,2,3,5  collagen  
special  receptors  (skin  doesn’t  respond   • Between  cells;  by  mesenchymal  
to  TSH)   cells  
o damaged  cells  -­‐>chemical  mediators  -­‐>   b. Basement  Membrane  
vasoconstriction,  attraction  of  WBCs   • Where  cell  sits;  gives  
  organization  (cells  grow  only  
a. Paracrine  s.  –  surrounding  cells   upward)  
b. Autocrine  s.  –  self/same  cell  type   • By  Type  4  nonfibrillar  collagen  
c. Synaptic  s.  –  neurons  -­‐>  inc.  NTs   &  laminin  
d. Endocrine  s.  –  bloodstream  (hormones)    
    EXCEPTION:    
    CANCER  CELLS  (invades  Basement  Membrane)  -­‐>  grows  
V.  SIGNAL  TRANSDUCTION  PATHWAYS  (CELL  SIGNALING)    
downward  -­‐>  invades  blood  vessels  &  lymphatics  -­‐>  
• Signal  transduction  –  (+)  molecular  signals  [EC  to  IC]   metastasis  
 
*Signal  -­‐>  (+)  response      
*without  it,  it  is  useless       *NORMAL  CELLS  don’t  ivade  basement  membrane  J  
   
 
• Cellular  Receptors  
VII.  MAINTAINING  CELL  POPULATIONS  
o Receptors  with  associated  kinase  activity  
• Cell  Proliferation    
§ Receptor  Tyrosine  Kinase  (RTKs)  
o for  homeostasis  &  replacement  of  
o (-­‐)  Intense  Catalytic  activity  (immune  
dead/damaged  cells  
receptors,  cytokine  receptors,  integrins)  
• Key  elements  
o G-­‐protein  coupled  receptors  
o Accurate  DNA  replication  (for  normal  cell  
o Nuclear  receptors  
growth)  followed  by  equal  apportionment  of  
o Others:  Notch  family  &  Wnt  ligands  
DNA  &  other  cellular  constituent  to  daughter  
 
cells  
 
 
 
 
 
 
 
 
 

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PROPERTY  OF  AUF  SOM  BATCH  2019  
USE  AT  YOUR  OWN  RISK!   Page  4  
 
 June  27,  2016   Dr.  Gonzalo  B.  Roman  │  The  Cell  as  a  Unit  of  Health  &  Diseases  │  Pathology  
 
• Cell  cycle  
G1  –  presynthetic  growth  
§
S  –  DNA  synthesis  
§
G2  –  premitotic  growth  
§
M  –  mitotic  phase  
§
G0  –  quiescent  cells  not  actively  
§
cycling  
 
o Regulated  by  activators  &  inhibitors  
o Driven  by  CYCLINs  (>15)  D,  E,  A,  B  
o Surveillance  mechanism  
• Sense  DNA/chromosome  
damage  -­‐>  signals  apoptosis  
• If  it  fails  -­‐>  TUMOR  
• “quality  control”  
 
• Stem  Cells  
o various  differentiated  tissues  
o ADULTS:  
• replace  damaged  cells  &  maintain  tissue  
population  
• dies  d/t  shortening  of  telomeres  
 
o 2  Properties:  
• Self-­‐renewal  –  maintains  their  numbers  
• Asymmetric  distribution  
 
o 2  Varieties:  
a.  Embryonic  SC  
• most  UNDIFFERENTIATED  (no  
specificity)  
• @  inner  cell  mass  of  blastocyst  
• limitless  capacity  (totipotent)  
 
b.  Tissue  SC  
• adult  stem  cells  
• produce  cells  that  are  normal  
constituents  of  that  tissue  
 
Regenerative  Medicine  (Promising;  still  under  research)  
o stem  cells  to  repopulate  damaged  tissues/construct  
an  entire  organ  (Alzheimer’s  dse,  MI)  
o e.g.,  Myocardial  Infarction  -­‐>  decreased  cardiac  cells  
-­‐>  (+)  stem  cells  -­‐>  increased  cardiac  cells  
o known  to  be  successful  in  Bone  Marrow  Transplant  
after  chemotherapy  (hematopoietic  stem  cells  for  
leukemia)  
 
 
 
 

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