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Kennedy's Disease Chat Transcript 02-18-2006
Topic: Special Guest - J. Paul Taylor M.D., Ph.D. Research Update
Host: Bruce Gaughran
Bruce: Morning Terry
Murf: Morning Terry
kellyC_: hey good morning there mr. terry
fl-don: gm terry
TerryW: just got out of bed
Murf: Good turn out today!
Murf: too much info Terry ... LOL
Bruce: Terry, we are waiting for Dr. Taylor to join us. He had clinical rounds this morning.
Dart!: A good thing to do in the morning, Terry, and a good day to all!
MICH: Dart, are you in California?
Dart!: British Columbia, Mitch.
Bruce: For those interested, we have about 70 interested people in the upcoming clinical trial. That is a good response and we appreciate the interest.
kellyC_: yeah that's a great turn around bruce, yup
MICH: When will you know what med they're using for the trial?
Bruce: Dart, I love the Vancouver area and especially the San Juan islands.
craig_h: Bruce, do you know when people will be picked?
fl-don: i went through the ohio state clinical trial, and it wasn't all fun. got extremely weak during that trial
billeric: Bruce, If selected, will we need a local physical to make sure we meet the criteria?
Teddybob entered the room.
Bruce: We will be turning over the information when asked by the research team. We expect that to occur sometime in early March.
Dart!: I'll check in with you again, Bruce. This looks to be a chatty day coming up.
Bruce: More information will be forthcoming as we get closer to the trial.
Teddybob: Good Morning everyone! This is TJ, I could not get in the chat by my usual login name of doughboy
Bruce: For those just joining us, we are waiting for Dr. Taylor to join us. He had rounds this morning at the hospital and mentioned he might be a little late.
TerryW: TJ did you register for the new chat upgrade in the past 3 weeks?
Murf: TJ - what happened?
Teddybob: It's a little cold and nasty here in Houston today. I did Terry, don't know what happened
Teddybob: Morning Murf
MICH: TJ, I thought you were in Va
Gopher: appreciated the E-mail Terry on how to get on this week. I had trouble too
Teddybob: No Sir, my sister Louise is
Dart!: You provided a good door-key, Terry, but I found that my computer needed some Java to get it started thnis morning.
Teddybob: Hey Mich, I just stayed at her house when Murf and I went to NIH
Murf: ok Terry
craig_h: Snowing like crazy in my part of Virginia ................ugh
Bruce: Reference the trial, you can read more about the medication and other informationby reading the chat transcript from a month ago.
Denny entered the room.
Bruce: Morning, Denny. We are waiting for Dr. Taylor to join us. He had rounds this morning at the hospital.
Murf: Dart - would that be W40 motor oil? LOL
Teddybob: Hey Bruce, thanks for the info on the study done at the University of Ohio in 1990
Denny: Hi folks.
fl-don: bruce, where info on 1990 ohio study???
jpt entered the room.
TerryW: thee he is
Teddybob: I have to tell you that I'm thinking about going ahead with the testosterone treament, what do I have to lose?
Bruce: Morning Dr Taylor
jpt: Good morning everyone!
Murf: Morning Dr. Taylor
Bruce: This morning I would like to welcome J. Paul Taylor, MD, PhD, from the University of Pennsylvania, to our chat room. Dr. Taylor and his team are using the Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy (aka Kennedy’s Disease). In November, 2003, the KDA awarded Dr. Taylor's team a grant to help support his research project. In December, 2005, the KDA decided to again provide another grant to help Dr. Taylor's team continue their important work.
Bruce: In November, 2005, Dr. Taylor provided us with an update on his work and also commented: "We have made great strides with our work, in fact we have a manuscript on our Kennedy's Disease work that has received good reviews. This work was largely funded by (the) KDA and I have been anxiously waiting for this work to be accepted for publication before alerting you. I have also had two graduate students join my lab who are doing their Ph.D. thesis work on Kennedy's Disease."
jpt: Sorry for the delay, my office computer will not connect
Bruce: In recent discussions with several researchers, including two from the National Institute of Health, they once again reflected the importance of Dr. Taylor's research in helping to find a treatment and/or cure for Kennedy's Disease. Thank you, Dr. Taylor, for joining us this morning.
jpt: I have found a Mac down the hall that works
jpt: I'm glad to be here.
craig_h: Good morning Dr. Taylor, it was a pleasure to meet you in August
Bruce: No problem, we are happy you can join us today.
Bruce: Dr. Taylor, can you briefly bring us up to date on the research your team is conducting?
jpt: I want to express my gratitude to the KDA and members for so strongly supporting our efforts to understand KD
jpt: Yes, be glad too.
jpt: At the outset, when I first arrived here at Penn 2 years ago...
Murf: We have nothing to lose and lots to gain
jpt: we decided to invest a lot of effort into developing a fruit fly animal model of KD
jpt: the reasons for tis are myriad, but in brief, a fruit fly model allows us to take advantage of a powerful genetic approach to understanding KD
jpt: we have accomplished this by putting the human andrgen receptor gene into the fruit fly to make a "transgenic" animal
jpt: I can point you to a website tha features this
Bruce: That would be great, thanks
Bruce: Are other researcher's using your model?
jpt: so, this was very successful and we now can faithfully reproduce KD pathology in the fruit flu
Bruce: From a layman's perspective, could you discuss how does this help KD research?
jpt: if you go to www.med.upenn.edu/ins/ you will see the web page
jpt: please click on the link for "Featured Lab of the Month" at the top
jpt: the uses for this fly model of KD are extensive...
jpt: most practical, we can set up large colonies of these flies to be used in drug screens...
Murf: Ya'll can meet Dr. Taylor in person when you attend our KDA 2006 conference in Atlanta GA this year. Dates are October 11-13 2006. Mark your calendar!!
Teddybob: My calendar and brother Bill's is marked
jpt: the fly model can also be used to test proof of principle (yes, I'm coming!) for candidate drugs that are implicated from cell culture work or by usefullness in another disease
Murf: The flies will not be attending
jpt: I will bring movies of the flies though:)
Bruce: We'll look forward to it.
jpt: To get at KD, we need to know more about which biological/cellular pathways are adversely affected by the disease
Bruce: Do you share your flies with other researchers or do they come to your lab to test these drugs?
jpt: the old-fashioned approach was to think up likely pathways one by one and test them out experimentally
jpt: our flies are freely available and we have shared them with 4 or 5 labs so far
Dart!: I wondered 'why something so tiny for a test subject, but true, fruit flies are cheap and easy to transport, compared to even a small dog..
Bruce: I was shocked when I read the cost of developing mice with KD. It is my understanding that fruit flies are very reasonable.
jpt: back to the the approach thing...the flies enable us to use some "high throughput" "unbiased" approaches to discovering what's wrong in a motor neuron in KD
Teddybob: Dr Taylor, my name is TJ, my testosterone level is 164, my Diabetes Dr. wants me on a Testosterone treatment plan, what are the pro's and con's of doing this and the risks!
jpt: for example, we will do a "genetic modifier screen" this means taking the KD flies and introducing 10,000's of genetic mutations to look for genes that are involved in pathogenesis
jpt: let me try to catch up on some of these questions...
jpt: flies are cheap, presently we spend about $15,000 per year for everything
MICH: Are fruit flies automatically on fruit and only come to life if the fruits left out to spoil?
jpt: the cost with mice would likely be about 7-8x more expensive
jpt: fruit flies are drawn to ripe fruit (they smell it) and are very common in the wild
Gopher: How much longer can you use fruit flies ? What is the next step
jpt: to the testosterone question...
jpt: we have NO good evidence that testosterone is beneficial in KD
coak entered the room.
jpt: Hi John!
Bruce: Morning, John, we have Dr. Paul Taylor on today
jpt: I was saying...
jpt: we have NO reliable evidence that testosterone is beneficial in KD
coak: Hello all- give me a minute to read up where you all are.
Teddybob: does it do harm
jpt: we have THEORETICAL basis for thinking that it might be bad
jpt: there is no proof that it is particularly harmful to KD men, but no one has studied this yet
Teddybob: I understand it might be bad for motor neurons, what are they
kellyC_: wow very informative,,, medical stuff ,,,,
jpt: Teddy, you ask what is the basis or what are motor neurons?
Teddybob: What r motor neurons.
jpt: motor neurons are long nerve cells that extend from your spinal cord to your muscle
jpt: this is the neve cell that fires to make your muscle contract
Teddybob: So they control your muscles, okay Thanks
jpt: in KD the nerve cell becomes dysfunctional and eventually dies, leaving the muscle unable to contract
Bruce: The androgen receptors are part of the neurons? Is that correct?
jpt: we think the muscle cells are probably OK
coak has left the room.
coak entered the room.
Dart!: Would electrical impulses tend to reactivate those nerves?
Teddybob: Isn't it true the lower the testosterone the less energy you have?
jpt: the androgen receptor is a protein that lives inside the nerve cell
jpt: lots of cells have the androgen receptor protein, but motor neurons have more than most
billeric has left the room.
jpt: the androgen receptor sits around waiting for testosterone to come and bind to it
kellyC_: doctor taylor,,, does kd affect the muscles for E,D?? if you know what i mean.???
jpt: the binding of testosterone to androgen receptor somehow kicks off the disease
billeric entered the room.
jpt: since men have much higher levels of testosterone, they are affected by the disease
kellyC_: like motor neuron etc
Bruce: I believe I read that the testosterone clogs the androgen receptor and causes it not to function correctly. Is that correct.
jpt: women carriers would likely also get KD if they were to receive testosterone injections, something we obviously avoid
Teddybob: You are very informative and helpful. This is Great information So lower the Testosterone, the less the diseae affects you. Is right
jpt: Bruce, the muscle cells atrophy because of lack of stimulation by the motor neuron (motor nerve)
Teddybob: So would electrical impulses keep them going
jpt: to some extent the atrophy is because of lack of use, but the nerve also supplies growth factors to keep the muscle plump and strong... that would not be replaced by artificial stimulation
jpt: mmm, no the androgen receptor in KD patients tends to work mostly normally
Teddybob: Why do we tire out when we try to exercise using our muscles then
jpt: there is some reduced function, as you know, as indicated by the common finding of breast enlargement
Dart! has left the room.
jpt: but for the most part the androgen receptor (AR) works just fine despite the mutation
Dart! entered the room.
Teddybob: Can you explain why the breast get bigger?
jpt: the motor neuron and muscle work as a system called he "motor unit", this uit is prone to fatigue when there is dysfunction in either part, so you tire more easily
jpt: testosterone is responsible for male characteristics...
craig_h has left the room.
Teddybob: Thanks for that info, Dr. Taylor
craig_h entered the room.
jpt: absence of testosterone leads to female characteristics...
Bruce: We constantly hear about the pros and cons of exercise for a person with KD. I am a believer that some stimulation is far better than none, but over-stimulation is more harmful than no exercise. What are you thoughts on exercise?
Teddybob: So why not take treatments then
jpt: I'm with you Bruce... I advocate moderate exercise to try and keep the motor units as healthy as possible. walking, swimming, stretching, yoga, low impact aerobics, for example.
TerryW: Teddy I think most of those questions are more fit for a clinical doctor
Gopher: Is vitamin E helpful?
Teddybob: Okay, execpt most of them don't know squat about KD
jpt: but clearly, KD patients (like other patients with conditions affecting the motor unit) are more prone to fatigue and possible damage, so don't overdo it
TerryW: I understand
jpt: don't forget that I am a clinical doctor!
Bruce: So, Doctor, what is next for your research project?
jpt: I am more than happy to provide general recommendations like this - I do it all the time!
jpt: well, for the research...
Bruce: And we appreciate it. You have been an excellent resource to the KDA.
jpt: we are vaery excited about some new developments
jpt: this is kind of esoteric, so i will do my best to keep my inner geek in check
craig_h: geek away !
jpt: we want to know how motor neurons GET RID of polyglutamine-expanded AR
jpt: because if the elimination of this bad protein cold be accelerated it would likely be beneficial
jpt: there are two major systems for degrading protein in cells...
jpt: the first system (which has traditionally gotten all of the attention is called the ubiquitin-proteasome system (or UPS for short)
jpt: we have used the KD flies to show definitively that degradation of AR by the UPS is impaired by polyglutamine expansion
coak: JPT: We have an upcoming KDA Conference in Atlanta from Oct 11-13. Can we ask you to come and report in person on Thurs 10/12 and then stay over for a MD/Research discussion on the 13th?
jpt: this hypothesis has been around for awhile, but we are the first to show this in an animal
jpt: I plan to attend
jpt: the OTHER system (which has not gotten much attention yet) is called "autophagy"
jpt: auto phagy translates to "eat self"
jpt: this is a poorly understood system in which the cell can partition a small portion of itself and autodigest
jpt: we have known for some time that autophagy is used to recycle internal parts of cells (like an old mitochondrion, for example)
jpt: what we know suspect is that autophagy becomes largely responsible for removing clumps of AR aggregates in KD nd similar diseases that have protein clumps
jpt: in fact, we have also shown this in the flies
jpt: why do we care?
Bruce: Dr. Taylor has agreed to stay on another ten minutes. Thank you, Doctor
jpt: because we can ACCELERATE this with drugs
jpt: so, the basic idea is to get the real solid proof that AR clumps are removed by autophagy and then see how we can aument this
Bruce: So, a stimulated auto phagy cleans the motor neurons creating healthier muscles?
jpt: We will publish a paper soon in which we have treated the KD flies with a drug that is known to augment autophagy and it strongly blocks degeneration
Bruce: Great! We look forward to reading more about it once it is published.
MICH has left the room.
jpt: yes, autophagy is clearing out clumped AR (and other damaged proteins) to keep the cells healthy
Bruce: What other questions do you have for Dr. Taylor?
craig_h: so this is an existing drug ?
jpt: yes, this drug is a non-FDA approved drug that is in clinical trials for cancer
Bruce: Notice: Five minutes left in the chat.
billeric: How does the upcoming drug trials fit in with Dr. Taylors research
Gopher: Is vitamin E therapy helpful in anyway
Murf: Meet Dr. Taylor at the KDA Conference Oct. 11-13th in Atlanta GA
kellyC_: WOW- Thank You Doctor Taylor from saskatchewan.
jpt: vit E is NOT known to be helpful, but is very unlikely to be harmful
craig_h: Doctor Taylor, thank you for all your hard work and dedication
MICH entered the room.
jpt: no, thank you. we love to do this work, but frankly wouldn't even be able to do it without you guys
Bruce: Dr. Taylor, thank you for taking the time to join us today. This was a great chat and we all appreciate your time today and dedication in helping to find a cure or treatment.
Murf: Meet Dr. Taylor at the KDA Conference Oct. 11-13th in Atlanta GA (sails pitch)
Dart!: Let's don't let THIS doctor get away from us!!! This has been very informative, Dr.Taylor!
billeric: Thanks Dr. Taylor and thank you Bruce for hosting this
Bruce: Everyone, you heard Dr. Taylor. Because of your donations, we were once again able to fund this important research.
Bruce: Any more questions for the good doctor?
Murf: Thanks for all you have done from all of us at KDA
Teddybob: Great Chat!
kellyC_: wonderful chat
coak: Thanks to you all for the contributions and th Dr. Taylor for his contribution back to us!
jpt: I should tell you that this drug also seems to be working in diseases related to KD, like Huntington's disease. There is likely to be a clinical trial in HD depending on the toxicity profile determined from the currently ongoing cancer trials
Dart!: Side effects?
Denny has left the room.
jpt: defintely side effects with this drug
Teddybob: Is Lymes disease same symptoms as KD
jpt: we just don't know how bad yet
Gopher: Yes, Thank You!! Today was the first time my husband was with me during the Chat room . He is now ready to learn more about his disease and I am so appreciative to the KD organization
Bruce: I hate to do this, but we have imposed upon the good doctor long enough today. Come meet him personally in October.
jpt: i suspect e will have to develop a new drug with the good activities, but without the bad activities
jpt: OK everyone, thanks so much for having me
Dart!: Is it a case of 'better the devil that you know, than the devil that you don't know'?
Denny entered the room.
Bruce: Okay CHAT ENDS
Murf: Thank You
fl-don has left the room.
jpt has left the room.
Denny has left the room.
craig_h: thanks Bruce
MICH: Sorry the system kicked me off, what drug was Dr. Taylor talking about?
kellyC_: thank you Bruce bye all of my KD friends
Gopher: I think so and also an ALS scareEND CHAT