Updated Research and Knowledge - Cutting Edge

[mlamber5]

And secondly the only way to really attack this in the near term (before CRISPR and like-systems) is to find out what proteins/pathways are being activated and silencing them or up-regulate them. I could fill the next 30 posts with articles and information to explain... the information is free for all to research and draw their own conclusions on the internet but in my mind AGA comes down to 4 main factors in people of European ancestry. The first is Androgenic hormones themselves. The second is the Androgen receptor. The third is overexpressed STAT3/PStat3, especially as it relates to the bulge and dermal papilla. And finally the fourth is the cytokine Interleukin-6, which is pro-inflammatory and works mainly through the JAK/STAT3 pathway. It is the interplay of these four which I think is causing the entire phenotype we see in AGA, and the correlation/association between other at risk factors in those that have AGA such as BPH, Diabetes, Prostate Cancer, Parkinson's Disease, and much greater risk of idiopathic scoliosis in females (another 20p11 major at risk spot). Stoping Ar itself will merely slow down the progression of AGA. The only way we know of so far to stop it dead in its tracks is castration, and that obviously isn't an option. I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.

[TheKingofFighters]

[q] I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype. [/q]

On the Contrary- i do not think so.

[InBeforeTheCure]

So tell me, because this is a critical question that i could not answer myself- whether do we need to INCREASE OR DECREASE PAX1's expression in the balding scalp(in order to regrow hair)?

Compounds that decrease PAX1:

Cacitriol(inhibits b-catenin)
Copper
Acetominophen(Panadol)
Bisphenol A(an estrogenic chemical)
Testosterone(androgenic hormone)

That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):



(Bolton et. al, 2007, supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/16...omms11616.html

Strongest association in 20p11 with the ordinal assessment of nose wing breadth was observed for SNP rs927833 located in LOC100270679, a long intergenic non-protein coding RNA (LINC01432). There is substantial LD around this SNP and suggestive evidence of association (that is, P values <10−5), for SNPs over a region of ~400 kb extending to the Paired-box gene 1 (PAX1; Fig. 3f), a strong candidate gene in this region. PAX1 is a key developmental transcription factor which has been shown experimentally to affect chondrocyte differentiation through its participation in a regulatory pathway that also includes RUNX2 and SOX9 (ref. 46). More broadly, a Pax-Six-Eya-Dach (Dachshund) network, involving protein–protein and protein–DNA interactions impacting on a range of basic developmental processes has been described47. As indicated above, another PAX gene (PAX3) has been twice reported to impact on nasion position9, 11, and we replicate that association here. A missense mutation in PAX1 has been shown to cause autosomal recessive oto-facio-cervical syndrome, a disorder characterized by various skeletal and facial abnormalities48. It has also been reported that mouse embryos with Gli3-null mutations display drastically reduced Pax1 expression, possibly mediated through Gli3’s involvement in the sonic hedgehog signalling pathway49. Consistent with these experimental findings, we observe a significant statistical interaction of the GLI3 and PAX1 index SNPs on nose wing breadth (P value=0.005, Supplementary Table 17).

So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this.

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.

All these implies that PAX1 needs to be DECREASED in order to regrow hair- because a decrease of PAX1 is what gives females a curved spine, but protection from hair loss.

But, im confused because PAX1 is involved with the profileration of stem cells

http://dev.biologists.org/content/141/4/737

It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).

So is it an INCREASE or DECREASE of PAX1(which is expressed in the adult scalp) to regrow hair?

Any1 who can answer this question accurately has basically- found the cure to AGA because in those who have carry no other AGA-susceptibility genes(e.g AR/EDAR, HDAC9, etc locus) other than the PAX1 variant- needs only to address this gene in order to regrow hair.

Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.

In my opinion this is the critical issue in AGA. What in the heck is going on at 20p11? Ar variants only confer greater risk to those of European heritage, it is monomorphic in Asians (existing in roughly only 1 type). 20p11 is by far the greatest at risk spot in asians, and is by a wide margin the second biggest risk point in Europeans. So it is the commonality between the two (along with androgenic hormones themselves... NOT androgen receptor.... only in europeans does this somehow accelerate the process).

http://www.hair-gel.net/

Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/

Although this is in mice, this is a highly useful website. In postnatal mouse skin, PAX1 is primarily expressed in the dermal papilla and in a smaller amount in the dermal fibroblasts. But I think we must be careful here on this. The set of SNP's at 20p11 are between PAX1 and FOXA2. The SNP's do lie closer to PAX1... But i'm not sure in which direction the DNA is being read on this strand... aka from PAX1 to FOXA2 or from FOXA2 to PAX1. That can make a big difference. Although FOXA2 is not expressed in postnatal mouse hair follicle environment, a quick look up of the functions of FOXA2 shows that IT HAS TO BE INVOLVED SOMEHOW IN AGA. FOXA2 is involved in ANDROGEN METABOLISM and response to IL-6... you can google these if you like for proof. IL-6 has been shown to be induced by DHT in AGA dermal papilla and it increases expression through p-STAT3 in the ORS and the bulge to induce premature Catagen. Stat3 is also present in dermal papilla and in other tissues has been known to up-regulates Ar gene expression and sensitivity to Androgenic hormones. So in my mind, even though FOXA2 isn't explicitly expressed in mouse postnatal hair follicle.... FOXA2 must be involved in some way in the parthenogenesis of AGA... There is still a lot we do not know about genetics especially when it comes to "junk" DNA (The DNA not directly involved in gene expression or protein coding.... It has a function science just isn't entirely sure how to read it yet). And that is exactly what we are dealing with at 20p11 and AR/EDA2R ( At risk SNP's are between genetic coding on "junk" DNA ).

I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.

And secondly the only way to really attack this in the near term (before CRISPR and like-systems) is to find out what proteins/pathways are being activated and silencing them or up-regulate them.

I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

[mlamber5]

[q] I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype. [/q]

On the Contrary- i do not think so.

Thanks for your contribution

[mlamber5]

Looking forward to it. I can see we both have started from the same point, the genes it looks like. If indeed JAK/STAT inhibition does end up reversing AGA it would only make sense that the team that discovered the key pieces of information and cure to hair loss ( Christiano's team ) is a team that focuses on the genetics behind all types of hair loss.

[TheKingofFighters]

Atually, the possible cure- is in our vomit

[TheKingofFighters]

That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):



(Bolton et. al, 2007, supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/16...omms11616.html



So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this.

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.



It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).



Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.



Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/



I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.



I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

Atually im trying to look from an angle with the viewpoint that the AR is not the culprit of AGA- but rather, it's either an underexpressed, overexpressed or no expression of PAX1 binding to it that is causing AGA. It is also the likely explanation why blocking the AR only halts AGA at best- but does'nt regrowth any hair

BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).

[TheKingofFighters]

[q] Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh. [/q]

BTW, its:

SHH => Noggin <=> Pax1

Sonic hedgehog induces Noggin, which then induces Pax1's expression. But there was a study that stated Pax1 was upstream of Noggin.

So you are right in that Pax1 is a gene target of Hedgehog signalling

[TheKingofFighters]

Atually im trying to look from an angle with the viewpoint that the AR is not the culprit of AGA- but rather, it's either an underexpressed, overexpressed or no expression of PAX1 binding to it that is causing AGA. It is also the likely explanation why blocking the AR only halts AGA at best- but does'nt regrowth any hair

BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).

In other words, Dut/Fin can only merely be slowing down the inevitable(by staying as the less potent androgen receptor-binding Testosterone instead of converting to DHT)- they can never reverse anything.

[TheKingofFighters]

That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):



(Bolton et. al, 2007, supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/16...omms11616.html



So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this.

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.



It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).



Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.



Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/



I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.



I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

part of the solution to the puzzle lies in the Gluccocorticoid receptor too.