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  • (upbeat, bright music)

  • - Hi, I'm Dr. Joshua Beckman, and I am the

  • chair of the PVD council of the AHA.

  • I'm speaking to you from the ATVB, PVD, FGTB,

  • annual scientific sessions.

  • Today it's my pleasure to talk to you

  • with Dr. Gary Fitzgerald.

  • He's our distinguished lecturer and has given

  • a wonderful lecture on molecular clocks

  • and cardio-metabolic disease.

  • Dr. Fitzgerald, can you tell us what

  • a molecular clock is and how it relates

  • to metabolic disease?

  • - Molecular clocks are present in almost all

  • of our tissues.

  • Not present in the testes, for some reason

  • that has yet to be discerned,

  • but there is a central clock

  • in the suprachiasmatic nucleus in the brain,

  • and peripheral clocks can be entrained by

  • the central clock to maintain a 24-hour rhythm.

  • It's an interesting connection,

  • it's a little like an orchestra.

  • The peripheral clocks have the capacity

  • to follow the instructions from the center,

  • but also have the potential for autonomy.

  • Furthermore, we find that peripheral clocks

  • can send signals back to the brain

  • to entrain central function.

  • So, it's very much like a concert master in an orchestra

  • where everyone has the capacity to play on their own.

  • Generally, they follow the concert master's orders,

  • but their way of playing can influence the way

  • the concert master performs his duty as well.

  • - And so what's the link to cardio-metabolic disease?

  • - Well, clockworks are a very interesting

  • biological network.

  • They play an important role in knitting together

  • biological networks across organisms.

  • Therefore, when they break down,

  • we get the display of metabolic dysfunction,

  • as in a metabolic syndrome.

  • We get disordered response in terms

  • of immunoregulation, so we get inflammation,

  • and disordered clockworks have been

  • implicated also in aging.

  • - Is it possible that there is a centrally

  • dysfunctioning clock that then drives others,

  • or is it usually a pattern of clock disturbance

  • that causes disease?

  • - So, we know from, In terms of that question,

  • most of what we know actually derives from work in mice.

  • We and other people have disabled the one

  • non-redundant core clock gene, Bmal1,

  • in multiple tissues by now.

  • We know that disabling it in the center disorders

  • alternating rhythms, but you can knock it out

  • selectively in vascular muscle cells and

  • endothelial cells, in adipocytes and in the liver,

  • and get an array of different expressions of elements

  • of the metabolic syndrome.

  • - Okay, and has this work moved into the

  • human investigational room yet?

  • - We're very excited particularly about that.

  • So, most of what we know in humans so far

  • derives from what are called forced desynchrony

  • protocols, where people are studied under

  • very controlled circumstances.

  • The amount of time they have available

  • to sleep is regulated and disordered.

  • These forced desynchrony protocols allow us

  • segregate endogenous rhythms of the molecular clock,

  • and rhythms driven by environmental cues,

  • most of which we don't understand.

  • We've been very informed by that type of work,

  • but we've also been interested to see if we can

  • discern circadian rhythms in humans in the wild.

  • In other words, is there a sufficient signal

  • for us to be able to detect circadian patterns

  • against the noise of the diversity of human behavior?

  • We've recently completed a pilot study in

  • a small number of individuals, where to our surprise,

  • we've been heartened by the fact that we can see

  • diurnal oscillation in the micro-biome, for example,

  • in elements of the metabolim and proteam

  • as well as the genome, and we've integrated that

  • with multiple approaches to remote sensing.

  • So, we're encouraged to project this study

  • onto scale, and to look with sufficient power

  • to characterize what we call the

  • physiological pronobiome, and it's important

  • to do that because we need that information

  • before we can start looking in an unbiased way

  • for mechanistic information that might explain

  • the time dependent expression of disease,

  • and we know that, for example, diseases like asthma,

  • myocardial infarction, stroke, depression,

  • they all osculate, even aches and pains

  • in your joint due to the cartilage clar,

  • they all osculate as a function of time of day

  • in terms of their expression, but we have very little

  • understanding of is the mechanistic explanation of that.

  • - That's a pretty incredible journey

  • from the bench to the bedside.

  • I think the lecture's absolutely spectacular,

  • and hopefully you'll get to look at it online

  • at another time.

  • Thank you very much for you time.

  • - Thanks very much, Josh.

  • (upbeat, bright music)

(upbeat, bright music)

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分子鐘在心血管疾病中的作用 (The Role of Molecular Clocks in Cardiovascular Disease)

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    Amy.Lin 發佈於 2021 年 01 月 14 日
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