Cilia, Congenital Heart Disease & Genetics - The Brueckner Lab at Yale School of Medicine

Transcript

• 00:05If you look at us
• 00:07on the outside, we're pretty
• 00:09symmetrical.
• 00:09But if you look on
• 00:10the inside, we're incredibly asymmetric.
• 00:13And the most asymmetric thing
• 00:15is our heart.
• 00:17Early in development, you have
• 00:18a head and a tail
• 00:19and a front and a
• 00:20back, but you don't have
• 00:21a left and a right
• 00:22and you need the embryo
• 00:23to have this internal reference.
• 00:26Cilia are these little structures
• 00:29that are stuck on the
• 00:29top of every cell. So
• 00:31what the embryo does is
• 00:33it takes these very asymmetric
• 00:35cilia
• 00:36and positions them on a
• 00:37group of about two hundred
• 00:39and fifty cells
• 00:40that come up at about
• 00:42eighteen days of human
• 00:44gestation.
• 00:45And now those cells
• 00:47have their own internal reference.
• 00:48Oh, I am asymmetric. This
• 00:49is my left side. This
• 00:51is my right side because
• 00:52the cilium on top of
• 00:53me points the way. And
• 00:55that mechanical signal is then
• 00:57transmitted to the whole rest
• 00:58of the embryo, including your
• 01:00heart, your lungs,
• 01:02your liver, your gut, etcetera,
• 01:04etcetera, to tell them, oh,
• 01:05this is left and this
• 01:06is right.
• 01:11So we're part of a
• 01:12national consortium
• 01:14that is essentially trying to
• 01:15build
• 01:16the largest congenital heart disease
• 01:19database,
• 01:19and we have recruited a
• 01:21total of about seventeen thousand
• 01:22patients. And what we're trying
• 01:24to do now is link
• 01:25that genetic cause to a
• 01:28developmental mechanism that makes the
• 01:30heart develop improperly.
• 01:31So my lab is focusing
• 01:33on cilia, which we've turned
• 01:34up in the genetic analysis
• 01:36also
• 01:37as a significant cause of
• 01:38human congenital heart disease.
• 01:41We're trying to see how
• 01:42they impact not just whether
• 01:43your heart's on the left
• 01:44or the right, but also
• 01:47they might impact heart function.
• 01:48We know that they impact
• 01:50early valve development,
• 01:52And those are places where
• 01:54you could imagine
• 01:55that you could have some
• 01:57potential to intervene and make
• 01:59things better.
• 02:03We go from two angles.
• 02:05The first angle is the
• 02:06large scale genomic studies. So
• 02:07a lot of our work
• 02:08was supported by Yale Center
• 02:10for Genome Analysis.
• 02:12And so one aspect works
• 02:14through the geneticists
• 02:15and the more statistical genetics
• 02:18approach to defining what the
• 02:20contributing causes are.
• 02:22And the other aspect, we
• 02:24work with models to try
• 02:26to better understand how the
• 02:28genes we identify in humans
• 02:30actually function in heart development.
• 02:33And we're trying to determine
• 02:35at what point in development
• 02:37the heart has its very
• 02:39earliest
• 02:40structural
• 02:41left right asymmetry
• 02:43and how those early signals
• 02:45from the ciliated cells cells
• 02:47in the left right organizer
• 02:49communicate to the developing heart
• 02:51tube to make it go
• 02:52left or right.
• 02:57Our hope is that we
• 02:59can first
• 03:00really understand the genetic architecture
• 03:03of congenital heart disease on
• 03:05one hand,
• 03:06and then understand
• 03:07how the heart develops, especially
• 03:09in its most early steps,
• 03:11to understand the molecular mechanism
• 03:14that drives heart development. And
• 03:15understanding
• 03:16that will give us some
• 03:19cues
• 03:20as to
• 03:22which patients might respond to
• 03:24what therapy. I mean, we
• 03:25can't make the heart loop
• 03:27in the other direction
• 03:29because that happens at twenty
• 03:31days of human gestation,
• 03:33but we can help deal
• 03:34with the outcome
• 03:36postnatally.