LEINWAND, Leslie, Python Snake Heart Metabolism, U Colo, April 21, 2015
<p class="MsoNormal" >LEINWAND, Leslie, Python Snake Heart Metabolism, U Colo, April 21, 2015</p>
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(I sit with one of her former grad students: Martin Guess (who is now in Tom Rando's Lab)..mgguess@stanford.edu)</p>
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Intro by Joe Wu.</p>
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This is a CVI noon seminar on Tuesday in LKS 130.</p>
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She is CSO of BioFrontiers Instit at U Colo Boulder;</p>
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she is Prof of Molec and Cell and Dev Bio.</p>
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her formal title is <b>translating the extreme biology of Pythons to Mammalian Hearts</b>.</p>
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cartoon: you are here (shows two rats looking at a slide of python with a lump in its
middle (with worried looks)</p>
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Python as a model organism...</p>
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drug from animals with extreme bio</p>
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she shows vampire bat</p>
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Draculin is an anticoag drug derived from vampire bat saliva !!!</p>
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also shows Gila monster</p>
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Byetta is a DM drug derived from Gila monster</p>
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Conus toxins... from poisonous snails...</p>
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for anti-stroke, pain drugs...
from Conus paralytic snails</p>
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human can die within 7 to 10 mins ...
these snails have harpoons...</p>
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look exactly like a manmade harpoon (with hundreds of peptides)</p>
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try to harness the natural world for rx.</p>
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Burmese pythons...</p>
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(from India and SE Asia)</p>
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perhaps a million snakes in the Everglades.</p>
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not venomous... they are only constricting</p>
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20 to 30 feet long...</p>
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can live 20 to 40 years.</p>
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can go 12 months wihtout eating...</p>
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they can eat 100% of their body mass in ONE MEAL.!!!</p>
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shows Python eating a kangaroo.</p>
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face goes in first (to avoid getting bitten)</p>
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why pythons for her work...</p>
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Jared Diamond (Guns, Germs, Steel; Collapse, etc)</p>
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post feeding response:</p>
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compares pythons vs mammals</p>
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insulin secretion in fed state goes up by 41X versus 5X in mammals</p>
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metab rate 44X versus 1.5X
Triglycerides 160 X versus 1.7 X</p>
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so, metab of snake goes up as if doing horse race for 6 days straight.</p>
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every organ does that (doubles in size within 24 hours) after eating large meal...</p>
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but returns to fasting within a few days.</p>
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no predators (xc humans)</p>
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get as big as they can, as fast as they can (their evol drive)</p>
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digestion of a rat is hardly begun at 24 hours....</p>
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they are building new tissue (not simply swelling w fluid)</p>
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shows xrays of rat inside python...</p>
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shows snakes liver... it doubles in size!!! (after feeding)</p>
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we grow snakes as babies and then grow them to adulthood ... at abt 6 feet long..</p>
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(Marty, her snake handler, is seated next to me!)</p>
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we did a survey of reptilian hearts: all v fibrotic...</p>
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collagen content is 15X as high as mammalian heart (v stiff heart)</p>
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two kinds of heart growth in humans</p>
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chronic exercise (a la Lance Armstrong and Michael Phelps) versus</p>
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that due to HBP and genetic heart disease...</p>
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(so, what's going on with python hearts (and they live 20 to 40 years!)</p>
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what are the molecular mechs of this large organ mass incr and then regression?</p>
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The fed heart undergoes CELLULAR enlargemnt (not cell division)</p>
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it is negative for BrdU staining (ie no proliferation of heart cells)</p>
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it gets bigger by cell hypertrophy (not by prolfieraiton)</p>
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Signaling pathways...</p>
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python genome has not been annotated;</p>
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she shows benefic signaling moleculs that are activated (post feedin)</p>
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pAkt and and total Akt...</p>
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(just as in an exercised mouse)</p>
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the key idea:</p>
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clinically, exercise is benficial in the setting of heart diease...</p>
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however, many people cannot exercise enuf to get the CV benefit.</p>
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goal is to provide CV benefit if a person cannot exercise enough...</p>
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(goal... activate benefit pathways in a diseased human heart)</p>
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shows accumulation in fed python plasma...</p>
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shows milky plasma at 24 hours...</p>
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(like Morgan Spurlock)</p>
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Morgan Spurlock's rule...</p>
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ate McDonalds 3 meals per day for 30 days and that made Morgan Spurlock sick...</p>
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he was quite sick after 30 days...</p>
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McDs STOPPED SUPERSIZING after his documetnary...</p>
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why doesn't python get sick???</p>
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our initial (wrong) hypoth was that ....</p>
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actually postprandial heart is burning fuel like craxy...
it has huge incr in oxidative capcity...</p>
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we did not see enhanced ROS...</p>
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postprandial heart is protectedf form oxidative stress by upreg of SOD2 eg.</p>
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can this cardiac growth be translated to mammalian heart
(by putting python plasma on rat heart cells.</p>
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YES... it worked (grad student did unauthorized resch!)</p>
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so, what genes mediate this mammalian cardiac myocytes growth?</p>
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we did transcirptome analysis.</p>
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most potent regul is aquaporin7 = AQP7...</p>
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python plasma potentlyu upregs AQP7 in mouse heart.</p>
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it is a water glycerol pore.</p>
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showed that AQP7 mRNA expression is consistent with cardioprotection...</p>
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it seems to be cardioprotective...</p>
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and Mice that have NO AQP7 are OBESE and diabetic...
shows pic comparing the mouse to wild type.</p>
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Japanese reesch: AQP7 is cardioprotective...</p>
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we have made a cardiac-specific Aqp7 null mouse.</p>
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prolonged CRE expression itslef results in cardiotoxicity . a word of caution...</p>
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so, what is it in the snake plasma that induces myocard hypertorphy.</p>
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shows 3 fatty acis that incr in fed plasma...</p>
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palmitic, myristic and palmitoleic.</p>
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Palmitoleic acid is RARE in rodent and human food (unlike myristic (coconut) palmitic (eg salmon)</p>
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(may be from microbes)</p>
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can we substitute fed postpradial FAs = fatty acids to get rat cardiac cell hypertrophy...</p>
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the 3 fatty acids DO recap the growth induced by snake plasma...</p>
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(it IS the FAs)...</p>
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next expt... add 3 FAs on mice... will that do it?</p>
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yes FA infusion triggers cardiac hypertrophy in mice (and in pythons)</p>
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it IS specific to this mix of FAs...</p>
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yes... do get incr AQP7 and incr IGF1 (also good)...</p>
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(change title to Pythons and Heart Failure)</p>
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ARVMs = adult RV myocytes... do get incr in many signaling pathways from FAs.</p>
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conclusion: FAs promtoe benficial growth of cardiac cells.</p>
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our preclinical studies:</p>
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will pre-rx with FAs prevent disease (such as MI and pressure overload)</p>
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will FAs be therapeutic in heart disease?</p>
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(but what is dose and rx schedule)...</p>
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snag with govt...</p>
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Burmese pythons labeled as invasive species (cannot ship across state lines)</p>
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persuaded govt to give them exemption.</p>
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but Oklahoma brreder also need license (not yet)</p>
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none in Colorado.</p>
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</p>
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are pythons protected from metab syndrome?</p>
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again shows Morgan Spurlock... in 30 d he gained 24 lbs and
his chol went from 168 to 230
MD said "Morgan: you must stop!"</p>
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Super Size Me (a film of epic proportions)</p>
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can we supersize our pythons?.</p>
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feed the pythons as much as they will eat as often as they will eat for 3 months</p>
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(the undergrad doing this work gave up after doing this... now works for Apple)</p>
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will they become obese and DM?</p>
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(feeing 6 to 8 adult rats at a time)...</p>
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UG is now a vegetarian! Ryan did this)</p>
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if exposed to this daily (as in Everglades)</p>
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they did NOT become DM .
these snakes became unbelievably. aggressive...</p>
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Supersize-me snake is v aggressive and big (as in the everglades)...
they just got huge but no bad metab or heart probs...
hearts did not accum lipids (the snakes themselves were huge, tho)</p>
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PETA started sending letters to U Colo Bd of Regents, etc.</p>
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Ryan Doptis did the supersize owrk...</p>
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Cecilia Riquelme...</p>
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resting heart rate of snake is 10 beats per minute</p>
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goes up to abt 70 postpradial...</p>
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(her U sono tech will not do snakes.. v snake phobic)</p>
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cannot get snake to go to sleep with isoflorane...</p>
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they can hold their breath for over an hour! (eg when underwater)</p>
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these FAs also incr insulin secretion...</p>
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</p>