STAT3

But, um, but all of those projects, whether it was the Lunar Outpost Commission, whe- uh, developing electromagnetic pulse weapons, the physics behind it, the, the chemical engineering on the applied side, being able to apply those, um, really fundamental, um, uh, tools to direct applications and, and, and problem-solving solutions really paid off.

And then in, um, in 2003, uh, I may have gotten a little too close to something, um, at one point in my life, but I had a bone marrow genetic problem with a JAK2/STAT3 mutation in my bone marrow, and got diagnosed with a, a, uh, a cancer called polycythemia vera.

And it's, was very rare.

There were only about 15,000 people.

Then JAK2 phosphorylation activates the PI3K-AKT pathway.

Then the JAK2 also activates the STAT3 signaling pathway.

What that means, roundabout way of saying, is that downstream, once this receptor is bound through using a peptide ARA290, downstream, we get reductions in TNF-alpha, interleukin-6, interleukin-1-beta, and MCP-1 receptor.

We also get upregulation in the anti-inflammatory interleukin-10.

They think from the chronic high blood pressure issues, the heart was working so much harder and it caused a little bit of an enlargement in my heart.

So when I get diagnosed with this polycythemia, And it was confirmed with what's called a JAK2 STAT3 mutation.

I was, to be perfectly frank, quite shocked.

I thought I was in pretty good shape.

By contrast, most other immune cell populations showed relatively little change.

The researchers also identified increased IL-6, JAK, STAT3 signaling as a potential mechanism linking altered immune regulation with liver fibrosis.

STAT3 phosphorylation was increased in whole liver tissue from older mutant mice.

However, primary hepatocytes isolated from these animals did not show the same change, suggesting that increased STAT3 activation primarily reflected infiltrating immune cells rather than an intrinsic alteration within hepatocytes.

Consistently, aged mice with hepatocyte-specific SHP1 deletion did not reproduce the abnormal B-cell and macrophage infiltration.

Thus, aging may act as a permissive factor that unmasks the pathological consequences of partial SHP1 dysfunction, facilitating the accumulation of B cells and macrophage subsets, as well as the progression towards fibrosis.

If TGF-beta is produced as a pro-inflammatory cytokine signature, it can go one of two ways from a naive CD4-positive T cell.

with the modulation of interleukin-6, then generating a STAT3 response, those cells will become Th17, Roar Gamma T transcription factor regulated.

And interleukin-21 will be produced from those nation Th17 cells, and that will promote more Th17 cells, essentially via proliferation.

Now, when that occurs, Antileukin 23 and STAT3 functioning will produce the fully mature TH17 cells, and they're going after, specifically, extracellular bacteria and usually fungi.

They'll be secreting cytokines antileukin 17 and antileukin 22.

Those will activate neutrophils, and when there's an excess of pro-inflammatory response in those cells, that's when you see autoimmune disease.

So I think it's a very interesting target because it's kind of been shown to kind of lead to preterm delivery.

It signals through STAT3.

So those are kind of like the mechanisms that I found is like IL-9 and STAT3 because STAT3 also signals through IL-6 and also signals through, you know, TLR receptors that respond to LPS.

So that's kind of the signaling pathway that I'm focused on right now.

But I think it's important to keep in mind that all of this exists in a context of a bunch of other cell types.