Samuel Sidi
Icahn School of Medicine at Mount Sinai, NY·Biochemistry
Cells decide whether to die or to mount an inflammatory response using large protein complexes that act as switches. Each complex senses a particular kind of damage and, when triggered, activates a cutting enzyme called a caspase that carries out the program.
- Fields
Biochemistry
Microbiology & Immunology
Genetics
- Topics
caspase-2
PIDDosome
ANKosome
- Grants
- 2 known grants, through Jun 2028
What they work on
- Identify which isoform of the cytoskeletal adaptor ankyrin-G nucleates the proposed 'ANKosome' complex with RAIDD and caspase-2, and use structure/function analysis to determine how cytoskeletal injury triggers its assembly.
- Test whether the ANKosome converts damage to the cell's protein scaffold into programmed cell death, in mammalian cells treated with cytoskeleton-targeted anticancer drugs and in live zebrafish embryos.
- Test whether the ANKosome drives death of mouse neurons exposed to beta-amyloid, the aggregating protein of Alzheimer's disease, using a collaborator's in vitro Alzheimer's disease model.
- Define how DNA breaks in the nucleus trigger assembly of the IRAK4-IRAK1 activation platform in the cytoplasm after ionizing radiation, testing the DNA sensor cGAS as the initiator downstream of ATR damage signaling.
- Identify the adaptor that nucleates the IRAK4/IRAK1 platform in place of MyD88, with the IRAK-interacting protein Pellino1 and the death-domain kinase DAPK1 as lead candidates, and determine how Pellino2 drives IRAK1 into the nucleus.
- Determine the biological role of non-canonical IRAK signaling by extending zebrafish and mammalian work to Drosophila, asking whether it is conserved in flies and whether it guards against unwarranted apoptosis from UV light or from DNA breaks made during meiotic and VDJ recombination.
More about the research
Which complex assembles, where in the cell, and in response to which insult determines the outcome. Both projects here dissect previously unrecognized signaling routes of this kind: one is a new activation platform for the enzyme caspase-2 that responds to damage to the cell's internal scaffolding, and the other is an unexpected job for an immune-signaling kinase in helping cells survive radiation. Both bear on cancer treatment, since chemotherapy and radiotherapy work by pushing tumor cells to die.
Why it matters
Both projects target mechanisms that determine whether tumor cells die from treatment. Non-canonical IRAK signaling has been implicated as a pervasive driver of tumor resistance to radiation therapy, so defining it could yield tests to predict which patients' tumors will resist radiotherapy and drug targets for overcoming that resistance. Defining the ANKosome could inform drug development for two problems common in aging populations: Alzheimer's disease, where caspase-2 is linked to beta-amyloid neurotoxicity, and tumor response to cytoskeleton-targeting chemotherapy.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Eric Ubil
University of Kentucky, KY·Microbiology & Immunology
Determine how tumor cells regulate secretion of proteins that activate the macrophage Mer receptor, and test whether their levels in human tumors predict response to chemotherapy.
Penghua Wang
University of Connecticut, CT·Microbiology & Immunology
Test whether unanchored lysine 48- and lysine 63-linked ubiquitin chains bind caspase-4/11 and promote its assembly and activation, using cell-free and biochemical assays.
Mohanish Deshmukh
University of North Carolina at Chapel Hill, NC·Neuroscience
Identify which brain cell types are most affected when miR-29, a microRNA that rises during brain maturation, is reduced in the adult mouse brain, using single-cell RNA sequencing and analysis of dendritic spines and neuron branching.
The school
Icahn School of Medicine at Mount Sinai: 45 labs on PI Pages, $1.0B a year on research, 62 research doctorates a year.
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