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Autophagy  i s   a n   e s s e n t i a l   p r o c e s s   f o r   l y s o s o m a l   d e g r a d a t i o n   o f   l o n g ‑ l i v e d  p r o t e i n s  and o t h e r  c e l l u l a r  c o m p o n e n t s  i n t o  a c t i v e  monomers t h a t  a r e  

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Mechanisms o f  Autophagy i n  t h e  Pancreas 

G r a d u a t e  S c h o o l  o f  P h a r m a c e u t i c a l  S c i e n c e s ,  D e p a r t m e n t  o f  D e v e l o p m e n t a l  G e n e t i c s   S a l l y  E l s a y e d  A l y  Mehanna 

Autophagy  i s   a n   e s s e n t i a l   p r o c e s s   f o r   l y s o s o m a l   d e g r a d a t i o n   o f   l o n g ‑ l i v e d  p r o t e i n s  and o t h e r  c e l l u l a r  c o m p o n e n t s  i n t o  a c t i v e  monomers t h a t  a r e   s u b s e q u e n t l y  r e u s e d  t o  m a i n t a i n  n o r m a l  tum o v e r  a n d  h o m e o s t a s i s .  Autophagy i s   s o m e t i m e s  c o n s i d e r e d  a s   a  s e c o n d  f o r m  o f  programmed c e l l   d e a t h  ( P C D ) ;  t h e   f a i l u r e  o f  a u t o p h a g i c  a c t i v i t y  i n  r e s p o n s e  t o  s t a r v a t i o n  o r  o t h e r  s t r e s s o r s ,  l e a d s  t o   c e l l  d e a t h .  T h i s  s t u d y  i s   d i v i d e d  i n t o  two main c h a p t e r s  t r y i n g  t o  i n v e s t i g a t e  t h e   r o l e  o f  two d i f f e r e n t  a u t o p h a g i c  p r o t e i n s  i n  p a n c r e a s .  

Chapter 1 :  

C a t h e p s i n  D (CD) i s   t h e  m

o rl y s o s o m a l  a s p a r t i c  p r o t e a s e  a n d  i s   w i d e l y   d i s t r i b u t e d  i n  t h e  c e l l s  of v a r i o u s  mammalian t i s s u e s .  CD  p a r t i c i p a t e s  i n  v a r i o u s   p h y s i o l o g i c a l  e v e n t s  s u c h  a s  r e g u l a t i o n  o f  programmed c e l l  d e a t h ,  a c t i v a t i o n  o f   e n z y m a t i c  p r e c u r s o r s ,  a n d  m e t a b o l i c  d e g r a d a t i o n  o f  i n t r a c e l l u l a r  p r o t e i n s  t h r o u g h   m a c r o a u t o p h a g y .  

To i n v e s t i g a t e  t h e  r o l e  o f  

CD 

i n  p a n c r e a t i c  a c i n a r  c e l l s ,  which c o n s t i t u t e  

t h e  e x o c r i n e  p a n c r e a s ,  we g e n e r a t e d  a n d  e x a m i n e d  mice s p e c i f i c a l l y  d e f i c i e n t  f o r  

CD 

i n   p a n c r e a t i c   a c i n a r   c e l l s  

(Crfl~·Spink3crel+

m i c e ) .  

Crf!~·Spink3crel+

m i c e  

showed n o r m a l  p a n c r e a t i c  d e v e l o p m e n t  a n d  a u t o p h a g i c  a c t i v i t y ,  a l t h o u g h  L C 3 ‑ I I ,  

which i s   a  m a r k e r  o f  t h e  a u t o p h a g o s o m e ,  a c c u m u l a t e s  i n  b o t h  p h y s i o l o g i c a l  a n d  

p a n c r e a t i t i s  c o n d i t i o n s .  M o r e o v e r ,  

Crf!~·Spink3crel+

mice l e a d s  t o  a c c u m u l a t i o n  o f  

m a t u r e d  c a t h e p s i n  B (CB) a n d  c a t h e p s i n  L ( C L )  which a r e   members o f  t h e  

c y s t e i n e  p r o t e a s e  f a m i l y .   We t h e r e f o r e  c o n c l u d e  t h a t   CD i n   p a n c r e a t i c  a c i n a r  

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