Kennedy's Disease Association

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Kennedy's Disease Chat Transcript  10-16-2010

Topic: Research Report - Study links normal function of protein to death of neurons - Guest:  Dr. J. Paul Taylor

Host: Mike Goynes

 

BEGIN CHAT

MikeG: Hey Bruce, I don't know what happened... I saw him there but it may have been from the test we did Thursday.
Bruce: Okay, that might explain it. Did you see my blog this week where I talked about my new (used) Honda VMI van?
MikeG: I see my message from Thurs... and I saw him sor a few minutes but then he went away...
MikeG: no - been a week from hell for me. Lots of software problems...
MikeG: none of them mine, of course.
Bruce: That is always fun ... NOT!
MikeG: Paula and I went to Orlando for a mobility expo last weekend - saw a nice Toyota van there!
Bruce: I bought a 2007 Honda EX van with the 10"" lowered floor and side entrance ramp. It only had 15,600 miles. It is really nice and gives me complete freedom once again to just go.
MikeG: I like the kind where you drive into the back and not the side.
Bruce: I could not justify a new van ... $60,000 (WOW) for a Toyota or Honda.
MikeG: YEP!
Bruce: I did a demo on a rear entry and did not like it because it would not allow me to drive.
MikeG: I did see the Honda there - it was nice too but, yes, cost prohibiting
Bruce: I installed the EZ-Lock system and it is so easy and convenient. We are taking it to Atlanta tomorrow to see the Georgia Aquarium with Cindy's folks.
MikeG: yeah, you need to be able to get out and get in the driver's side.
Bruce: Morning Paula
Paula: Good morning
Bruce: Is this how you talk with Mike when he doesn't listen?
MikeG: lol
Paula: No, I can move faster than him, so I just follow him around until he hears me
Bruce: I like that answer
Paula: :}
Bruce: Cindy has indented the back of my head ... it accomplishes the same thing.
MikeG: actuall we used to communicate all the time with IM when she worked at her office...
Bruce: Mike, ref. the van, I wanted something that I could just get in and go without concern or the need for Cindy just in case something happened to my strength.
MikeG: now we can talk between our home offices
MikeG: yep - good idea
MikeG: I'm just lucky I can still walk
MikeG: someday I'll need a van like that
Bruce: I warned her now that I can get away that I just might do that someday. She took it differently than I thought and said ""WHEN are you leaving?""
MikeG: :)
Bruce: My Braun Joey system has worked very well, but I am no longer safe when I have to unload it and load it.
MikeG: is that the elevator system?
Bruce: Paula, have things calmed down at work now that the third quarter is over?
Bruce: Yes, the Joey stores the chair inside. It has a lift (elevator).
Paula: Not really, we are in the process of doing third qtr payroll reports now and the final deadline for 2009 taxes was Friday
Bruce: No rest ... bummer
MikeG: yep - that's what I have. Much more secure than the Freedom Lift I used to have.
Bruce: It worked great for me until I broke the tibia and fibula and could not transfer from the wheelchair to the driver or passenger seat.
MikeG: I hope the parser I wrote will take out the cutesy flower stuff that she has... for the transcript. If not, I'll have to re-write it.
MikeG: yep - that would be a problem!
Bruce: I also bought a 2007 Yamaha Drive gas golf cart this week to help me get up and down our hills. I burn through batteries quite often in the EZ-Go.
Paula: Oops. Should I change it?
MikeG: no - you're ok
Paula: There. It's gone.
MikeG: it will be a good test.
Paula: I can always put it back later.
MikeG: do all o0f you girls have stuff like that?
Bruce: The cooler weather is really starting to bother my muscles again. My left thumb has not worked well the last couple of days (low 40s) and the left index is getting weaker also.
Paula: No, just the ones who mess around with the buttons at the bottom of the screen:)
MikeG: :}
MikeG: we had a pair of 5s this morning here
Paula: Cold weather is hard on Mike, too. That's one of the reasons we are in FL
MikeG: it was supposed to get into the 40s but I don't think it did.
Bruce: I now have some of the aches and pain I have not felt for the last six months or so. My strength is not quite as good also. My brother swears by Arizona weather for helping keep him mobile.
MikeG: my habds don't work below 50
Bruce: For people like us who need to type and write, it becomes difficult. Yesterday, I was on a three hour conference call taking notes and just had to quit writing and use the keyboard. Most of my notes where not legible near the end.
MikeG: it gets pretty cold in Arizona though.
Bruce: He believes that it is humidty as much as cold that is the problem.
MikeG: I can't take notes at all anymore. Well - I can take them - just can't read them... :}
Paula: I'm not sure that'
MikeG: hey Terry
TerryW: Hi
Bruce: My company is doing away with their health insurance program at the end of the year. I am in the process of finding an alternative. I never thought a company as large as ours would do that, but profits always come before people.
Paula: sorry. I'm not sure that's totally a KD thing. I think it's probably part age and partly because we don't do nearly as much handwriting as we used to
Bruce: Morning Terry
TerryW: -Morning Bruce,
Paula: Hi, Terry.
Paula: How are you feeling?
TerryW: Hi Paula
Bruce: Well, I need to take a short break ...
TerryW: Overdone, getting everything ready for winter, rain
MikeG: sorry to hear that Bruce. Good timing though - November is open enrollment for Medicare part C
MikeG: I'm looking into that too
TerryW: We are getting 44 solar panels up on the stables for the property
MikeG: wow
MikeG: how many watts is that?
TerryW: Don't have them up yet but they say by end of month
TerryW: Average yearly is 875 kwh per month with as high as 1375 kwh in summer
MikeG: nice! can you sell back into the grid?
TerryW: yes
MikeG: kool!
TerryW: save up credits for months that we use more
MikeG: are you renting?
MikeG: hi Stan
TerryW: no we bought it
MikeG: WOW!!!
Stan: Morning everyone.
MikeG: what's the ROI?
TerryW: 40% rebates from state & fed
MikeG: nice
TerryW: but they are about to drop way down that is why we did it now
TerryW: 6 years mike
MikeG: that's what we did in the late 70s with our solar water system
TerryW: Our bill runs $450 in summer months
MikeG: not bad, not bad at all!
MikeG: ours would be 30 years
TerryW: Our electric rates have been going up 8% a year for the past 7 years
Gary_KC: Good morning. This is Gary Uchiyama joining in from Kansas City. It is a fine day but only 51 degrees this morning.
TerryW: hi Gary, stan
Gary_KC: Hi Terry!
Stan: Hi Terry
MikeG: I got a flu and pneumonia shot the other day...
MikeG: hi Gary
Bruce: Mike, I ended up with a Medicare Advantage plan that looks pretty good. I hope so anyway.
Gary_KC: Hi Mike.
MikeG: the pneumonia shot hurt for about a week!
Bruce: I got my flu shot last week also.
TerryW: got my shoy 3 weeks ago
TerryW: shot
MikeG: I need to talk to you about that Bruce...
Stan: Got my shots last week while at my doctor for regular visit. Got distemper too.
MikeG: I'm trying to decide
Bruce: Okay
TerryW: hi michael
MikeG: hi Mike
michael17860: Good Morning all
Bruce: I was upset that I am not eligible for Medigap until I turn 65.
TerryW: I may only be here in chat for a short time, We are taking Susannes horse down to the trainer to ride
MikeG: Today we are honored to have Dr. Paul Taylor, MD, PhD on our chat. Dr. Taylor is a physician-scientist working at St. Jude in Memphis. He used to see most of the hereditary neurological disorders at Penn, but 2 years ago he moved to St. Jude to do research full time. He’s been studying Kennedy’s disease for about 12 years. He has been previously been rewarded two KDA grants! He has a web-page (with limited content at present): http://www.stjude.org/taylor_jp
jpt: Hi everyone,
Bruce: Morning Paul
MikeG: Welcome to our KDA chat, Dr. Taylor.
jpt: thanks for having me
Stan: Good morning Dr. Taylor
Bruce: Paul is also a member of our Scientific Review Board
MikeG: thanks for being our guest! We have heard that you have some very exciting news for us... :}
jpt: We just published a paper that we have been working on for about 5 years...
jpt: and I think out results have imprtant implications for how we try to treat KD
Gary_KC: Dr. Taylor, I was excited for your new resarch paper.
MikeG: it sounds like several other diseases are targeted also, is that correct?
alexandre: Good Morning to all from Brazil
MikeG: hi alexandre
jpt: as many of you know, the dominant hypothesis in the field, not just KD but also other ""polyglutamine diseases"" as well, related to th formation of aggregtaes that may be toxic
TerryW: hello Alexandre
jpt: the question we asked ourselves 5 years ago...
jpt: was how a single mutation (polyglutamine expansion) could lead to so many different disease.
MikeG: hi Ed!
Ed M: Hello everyone
jpt: for example, the mutation that causes KD is the same as the mutation hat causes Huntington's disease, but they are nothing alike
alexandre: We are haveing a very important chat today with Dr. Taylor... thak you KDA!
jpt: in many of the poluglutamine diseases there are aggregates of the affected protein (although I don't think this has been formally shown in KD) and the feeling has been that this aggregation is causing the toxicity
jpt: but since the diseases look so different, we figured there must be something about each specific disease protein (the androgen receptor in KD) that specifies what cells are affected in each disease
jpt: the huge clue staring us in the face with respect to KD is the fact that only males are affected...
jpt: and we learned from several studies in 2002 that the basis for make specificity is higher levels of androgens in males...
jpt: and we puzzled over that for a few years, thinking maybe androgen binding to the androgen receptor (AR) promoted aggregation...
jpt: but that wasn't what we found...
jpt: another thing that normally happens when the AR binds hormone (androgen, testosterone, all synonyms for our discussion) it moves into the nucleus of the cell...
jpt: so maybe nuclear localization was necessary for the mutant AR to do its dirty work...
jpt: and that turned out to be true!
jpt: but why would that be???
jpt: one idea was that AR was more prone to aggregation in the nucleus...
jpt: or AR was more prone to cleavage in the nucleus.which might promote aggregation...
jpt: and that has been the placeholder hypothesis for many years now...
jpt: and this hypothesis has been he basis for treatment development strategies...
jpt: the idea has been to try and increase elimination of mutant AR by exploiting cellular protein degradation pathways...
jpt: and there's no doubt that accelerating the degradation of mutant AR is beneficial...
jpt: it's just hard to do outside a model system...
jpt: but we got to thinking...what is the actual [i]target [/i]of toxic AR in the nucleus???
JACK: Hello everyone
MikeG: hi Jack
jpt: is hormone binding the only normal function of AR related to development of disease???
jpt: the more we thought about it, the les likely it seemed that simple aggregation would be sufficient to differentiate KD from other disease with the same mutation...
jpt: and we decided to systematicaly evaluate every piece of AR that we could to see if any of them contributed to the development of disease...
jpt: to do this we needed to make hundred of different versions of AR, each differing by one or two amino acids
jpt: but we also needed a system in which to monitor the effect of all these changes
jpt: to make a mouse model of each, and evaluate the phenotype of each, was impossible for us. It would have taken 20 yeras...
MikeG: quite a challenge!
jpt: we could have used cell culture, but I have limited confidence in cell culture systems for KD for a number of reasons, and it's also a very non-physiological system...
jpt: so we used a simple animal model that has been the workhorse of genetics for over 100 years: the fruit fly!!!
jpt: as many of you know, we introduced mutant form of the human androgen receptor into fruit flies and they developed hormone-dependent neurodegeneration that correlated with polyglutamine length...
jpt: essentially, this is a ""fly model of KD""
jpt: this model captures all of the molecular events that are initiated by hormone binding and culminate in neurodegeneration...
jpt: flies are small, cheap, develop quickly, and have large litters...
jpt: so...we began making hundreds of transgenic fruit flies...each carrying a slightly different version of the human AR gene...
jpt: this project was mostly conducted by my graduate student Natalia Nedelsky...
jpt: with help from lots of folks, most notably Mara Pennuto...
JACK: The guys i work with areall in to body building. They all take one muscle building drink or anothe. Woul,d any of them be any good for us or would it do more damage the good?
jpt: and what we learned from this project was which portions of the AR were necessary for the whole toxic cascade to take place...
jpt: at first our results pointed to a few things that we already knew - like the fact that AR needed to be able to bind hormone and needed to be capable of transport to the nucleus - but this gave us confidence to continue...
jpt: subsequently we began to find a whole series of additional portions of AR that were important to the toxic cascade, and some regions that were essential...
jpt: most notably, we found that to be toxic, mutant AR had to be able to bind to DNA in the nucleus and also bind to transcription related factors...
jpt: this is the normal function of AR...to regulate gene expression at the genome level through the regulation of ""transcription"" - the process of making RNA that are later translated into new proteins...
jpt: now, I inagine that this may all sound pretty esoteric...
jpt: who cares if mutant AR has to bind DNA and transcription factors, right?...
jpt: well the reason this matters is two-fold...
jpt: first, it is a major onceptual change...indicating that the toxicity of AR, and the specific patter of disease that defines KD, is defined by the native function of AR...
jpt: blah blah blah...that part id for the technogeeks...
jpt: second, and of greater practical importance...
jpt: is the fact that it tells us that the way to block AR toxicity is to block normal function...
jpt: or at least some aspects of normal function...
jpt: we all know from mouse studes done by Gen Sobue 8 years ago that if male mice are deprived of all androgen they never develop disease...
poohsdaddy: I do not understand.... Please give an example to clarify.
jpt: our findings are competely consistent with that and in fact expalin is result...
jpt: clarify which?
poohsdaddy: Just go ahead.... I'll figure out what it all means later. Thanks, anyway.
jpt: no, letme see if some things need clarification. anone??
Gary_KC: Dr. Taylor, So far so good for me!
UTE: Great so far
jpt: I'm sorry if I'm making this sound complicated..it's actually prettty starightforward, just very challenging to explain in this format...
jpt: the thing to keep in mind is that the AR doesn't have one, single function...
MikeG: np - we can have our resident translator, Ed, explain later... :}
jpt: it interacts with many protein, probably hundreds, and carries out multiple functions...
jpt: I think it's likely that if we wiped out AR function altogether we would stop disease progression...
jpt: but I don't think that's a good strategy and here's why...
jpt: there's all kinds of good things AR is doing...even in KD patients...
jpt: in addition to maintaining males features...
jpt: its also contributing to strong muscle and bones...
jpt: so if we wipe out AR altogether it may be a net negative...
jpt: the question is whether we can inihibit some aspects of AR function (the parts that drive disease) while leaving the good parts intact...
jpt: sounds daunting, right???...
jpt: well, fortunately, we are not alone in this...
jpt: every big drug company out there is working on this...
jpt: why???
jpt: well, frankly, it's not because of KD...market too small...
jpt: although they're good people and would be delighted to inadvertantly develop treatment for KD...
jpt: they actually have their eyes on bigger fish...
jpt: like...
jpt: male pattern baldness...
jpt: prostate cancer...
jpt: endometriosis...
jpt: polycystic kidney disease...
jpt: there's a long list of conditions in which it is desribale to selectively inhibit certain function of the androgen recptor and leave the rest intact, but thise are the biggies...
jpt: now, it turns out that not only did our study inform us that [i]a[/i] native function must be targeted...
jpt: it also told us that we need to target a very specific region of the protein...
jpt: a small domain down at the very tip of the protein called ""AF2""...
jpt: it just so happens that this is a favorite target of the drug companies too...
jpt: so...what do we do now???
jpt: 2 big things
jpt: first, we must see whether my whole hypothesis is right...
jpt: many people think I'm wrong, by the way...
jpt: after all, our results came from an insect...
jpt: maybe things works different in humans...
jpt: that's the first big thing...to validate our results in a mammal
jpt: we are now making a small number of certain types of mice to re-test our hypothesis...
jpt: but if we don't follow up, who will? so we are pursuing the second big thing...
jpt: the second big thing is trying to identfy small molecule compounds that target AF2 (the small portion at the tip of the AR protein) to see if we can identify a drug that stops the bad activity of muatnt AR but leves the good stuff intact...
jpt: and that's where we are
jpt: let me step back and permit questions
Bruce: Very interesting and well explained. Thanks, Paul
Ed M: Yes, thanks Paul
Bruce: Paul, how long do you feel it will take to validate your findings in a mouse model?
jpt: good question...
jpt: we have made the transgenics already...but we are trying to confirm that they express the different versions of mutant AR i the right place a the right time. I expect within a year...
MikeG: Will your hypothesis counteract or reinforce the function of ASC-J9?
jpt: ahh, very interesting...
jpt: how does ASC-J9 work???
jpt: well, interestingly enough, there is conflicting evidence...
Bruce: Since other disorders also might have involvement with the AF2, does that mean that there are certain drugs out there already that could be helpful?
jpt: there is some evidence that it inhibits AR directly by interaction with AF2...
Bruce: Good
jpt: there is also evidence that it accelerates degradation...
Bruce: Bad...
jpt: those two observations are actually compatible...
jpt: because inhibition of AF2 binding to partners may be the way it destabilizes the protein and promotes degradation...
jpt: I actually think this is likely...
jpt: ASC-J9 works wonderfully in the fly model (we have not published this) and as you know it works well in a mouse model...
jpt: right now we use that as our gold standard...
MikeG: very interesting!!!
jpt: and it may turn out that we get fully behind ASC-J9 as the best candidate for a clinical trial...
MikeG: wonderful!!!!!!!!
jpt: but we don't want to settle on it until we test it head to head against other AF-2 targeting compounds (yes, there are many)
MikeG: is IGF-1 one of them?
jpt: IGF-1 is a different animal that may be a terrific amplifier of the kind of compound we are seeking...
jpt: because IGF-1 strengthens muscle and slightly inhibits AR function
MikeG: Amazing findings Paul! You’ve provided a mid-course correction that will possibly prove to be invaluable to finding a cure for KD.
MikeG: does anyone else have any questions for our good Dr. Taylor?
UTE: Off the wall question...we're talking good drugs...do we know of bad drugs...is it possible that a drug like cipro kills muscle protein in KD
jpt: we shall see...I hope so
MikeG: thanks for taking the time on your Saturday to update us on this very important finding, Paul. We DO appreciate you!!!
jpt: drugs with potential toxicity for muscles and nerves are risky in KD patients...
Bruce: Paul, as always, you make a great guest. We appreciate all that you do for the KDA and for all of us living with KD.
jpt: they can be used, but side effects must be monitored more closely
MikeG: will we see you in San Diego next month?
alexandre: Thank Dr. Taylor and Good bye all!
jpt: however, I don't think cipro is one of them...I'll check
loshimo11: Wow!!! Is this the first time we go over the allocated timeframe?
jpt: yes, see you in San Diego
jpt: bye all
MikeG: fantastic - see you then!
UTE: Thank you, quite enlightening info today
JACK: Thanks doctor
JACK: BYE ALL
Gary_KC: Dr. Taylor, thank you so much for your time to explain us your great resarch.
loshimo11: Gotta go... Last one out, please turn the lights off.
michael17860: Thank You Doc. Paul, Take Care and God Bless.
Stan: Thank you Dr. Taylor. It will take me a while to understand all this, but it sounds promising.
MikeG: Dr. Taylor will be at the KDA conference in San Diego next month so, if you haven’t registered yet, now is the time - you’ll be glad you did! Ed will translate for us… :}
UTE: Adios?


END CHAT