Cell Death Mechanisms, BCL-2 Proteins, & CAR-T Cells - The Katz Lab at Yale School of Medicine

Transcript

• 00:05Cell death is a key
• 00:07process that's necessary even in
• 00:09development in order to get
• 00:10a viable organism.
• 00:13This program is called upon
• 00:15again over and over in
• 00:16in almost every disease I
• 00:18can think of, where you
• 00:19either have diseases where there's
• 00:21too little cell death, such
• 00:23as in cancer,
• 00:25or you have diseases where
• 00:26there's too much cell death,
• 00:28such as in strokes or
• 00:29heart attacks.
• 00:35My lab is very interested
• 00:37in the process of cell
• 00:38death. That is how cells
• 00:40no longer survive. What are
• 00:42the things that cause them
• 00:43to die and then what
• 00:44are the molecular pathways by
• 00:46which they can die?
• 00:49So if we can determine
• 00:50the pathway by which those
• 00:51cells are being forced to
• 00:53die, we can then prevent
• 00:55that death and maintain the
• 00:56function of those cells.
• 01:01There are multiple different types
• 01:03of death pathways that one
• 01:04could,
• 01:05attack. We look at two
• 01:06in particular. One is the
• 01:08intrinsic pathway of apoptosis,
• 01:11which is mediated by a
• 01:12family of genes called BCL2
• 01:15family members,
• 01:16one of which we study
• 01:17that's really poorly understood is
• 01:19called BOC or b o
• 01:21k.
• 01:22BOC,
• 01:23unlike all the other BCL
• 01:24two family members which primarily
• 01:26act at the mitochondria, acts
• 01:27at the endoplasmic reticulum or
• 01:29the ER.
• 01:31BAC is important for ER
• 01:33stress,
• 01:34agents, and there are many
• 01:35different diseases which involve
• 01:38ER stress and or invoke
• 01:40it. And,
• 01:41tauopathies
• 01:42are one in particular because
• 01:44in this form of neurodegeneration,
• 01:47there's an overproduction of this
• 01:49protein tau, which then forms
• 01:52oligomers
• 01:53and causes a lot of
• 01:54ER stress.
• 01:56And as the name neurodegeneration
• 01:57implies,
• 01:58the main feature we see
• 02:00is loss of neurons, so
• 02:02death.
• 02:03If we learn exactly how
• 02:05Bach is mediating cell death
• 02:06within these neurons,
• 02:08then perhaps we can find
• 02:09a way to inhibit
• 02:11Bach's action and keep these
• 02:13neurons alive.
• 02:16The second way is the
• 02:18extrinsic pathway of cell death.
• 02:21That's where other cells are
• 02:23from the outside causing the
• 02:25death of the cells.
• 02:27So often in the immune
• 02:28system, T cells are known
• 02:30as killers. They kill other
• 02:31cells, and so they extrinsically
• 02:33cause the death of those
• 02:34other cells.
• 02:36And it was learned that
• 02:38in addition to infected cells,
• 02:40T cells are also killing
• 02:41cancer cells recognizing
• 02:43cancer antigens
• 02:44that are expressed.
• 02:46But
• 02:46not every cancer has a
• 02:48good antigen and a t
• 02:49cell receptor that recognizes it
• 02:51in order to kill it.
• 02:52And so people have made
• 02:54what they call chimeric antigen
• 02:55receptors
• 02:56or CAR T cells, and
• 02:58the most successful example already
• 03:01approved is going after B
• 03:02cell leukemias and lymphomas
• 03:05against a molecule called CD
• 03:06nineteen.
• 03:08What we've been very interested
• 03:10in recently is expanding this
• 03:12to beyond
• 03:13these blood cancers to solid
• 03:16tumors. And so we've been
• 03:17going after other targets that
• 03:19are expressed
• 03:20highly on solid tumors and
• 03:22trying to boost the activity
• 03:24of these CAR T cells
• 03:25to kill them.
• 03:33The overall goal of the
• 03:34lab really is the selective
• 03:37therapeutic control of cell death.
• 03:40I'm a physician scientist.
• 03:42I spend eighty percent of
• 03:43my time running this research
• 03:45laboratory. The other twenty percent
• 03:47of my time, I'm a
• 03:48hematopathologist
• 03:49where I'm diagnosing,
• 03:51lymphomas,
• 03:52leukemias,
• 03:53and myelomas
• 03:54within patients.
• 03:55And so I'm very familiar
• 03:57with the blood system and
• 03:59how it can produce cancers,
• 04:00but I'm also very familiar
• 04:01with the blood system and
• 04:02how it can be harnessed
• 04:03in order to,
• 04:05affect,
• 04:06cure.