Updated Research and Knowledge - Cutting Edge

[TheKingofFighters]

Nifedipine:



The powder is yellow and not a conventional white, as in the case of all https://en.wikipedia.org/wiki/Dihydropyridine -derivatives.

It is also described here in another patent(aside from the 1 on hypoxia which 1 linked earlier)

http://www.patentsencyclopedia.com/app/20150005291

This study (not sure if it's done by the same inventors to the patent above) talks about calcium channels and the hair follcile:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690395/

Abstract
The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2TS acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.

Keywords: hair follicle stem cells, bulge, calcium channel, VGCC

[TheKingofFighters]

Inbeforethecure please give me ur valuable input on the above

[TheKingofFighters]

Finally, Hypoxia increases intracelluar calcium levels(which is why the patent i linked suggested the usage of Nifedipine- it blocks L-type calcium channels and results in vasodilation- the latter a process similar to Minoxidil)- which c-fos and inflammatory processes are heavily dependent on.

Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter.
Berna N1, Arnould T, Remacle J, Michiels C.
Author information
Abstract
Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
Copyright 2001 Wiley-Liss, Inc.

Then continuing on hypoxia reducing expression of pro-hair growth genes:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827269/

Abstract
Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen availability and what are the molecular mechanisms maintaining pluripotency in these conditions. In this study we characterized the transcriptional and molecular responses of three hESC lines (H9, HS401 and HS360) on short (2 hours), intermediate (24 hours) and prolonged (7 days) exposure to low oxygen conditions (4% O2). In response to prolonged hypoxia the expression of pluripotency surface marker SSEA-3 was increased. Furthermore, the genome wide gene-expression analysis revealed that a substantial proportion (12%) of all hypoxia-regulated genes in hESCs, were directly linked to the mechanisms controlling pluripotency or differentiation. Moreover, transcription of MYC oncogene was induced in response to continuous hypoxia. At the protein level MYC was stabilized through phosphorylation already in response to a short hypoxic exposure. Total MYC protein levels remained elevated throughout all the time points studied. Further, MYC protein expression in hypoxia was affected by silencing HIF2α, but not HIF1α. Since MYC has a crucial role in regulating pluripotency we propose that induction of sustained MYC expression in hypoxia contributes to activation of transcriptional programs critical for hESC self-renewal and maintenance of enhanced pluripotent state.


To clarify the mechanisms how hypoxic growth conditions contribute to pluripotency and differentiation of hESCs, we surveyed the transcriptome data for all transcripts associated with regulation of hESC physiology. Importantly, 12% of all oxygen-regulated transcripts detected were linked to mechanisms controlling pluripotency and differentiation [42] (Figure 3C). The majority of transcriptional responses were detected in prolonged hypoxic culture. From these genes of particular interest are HEY2 with a role in notch signaling [43], LEFTY2 involved in TGFβ-signaling [44] and IGFBP2 which is overexpressed in the stem cell compartment of glioblastomas promoting proliferation and survival of brain tumors [45]. Moreover, the levels of MYC that contributes to induction and maintenance of pluripotency [21]–[24] were elevated.

Hypoxic culture conditions also modified the expression of genes driving cell differentiation (Figure 2C), further supporting an idea that hypoxia directly influences the differentiation potential of cells. Among these genes were neuroectoderm marker PAX6 [46], trophoblast and placenta associated transcription factor MSX2 [47], and a primitive streak marker FLRT3 [48], which all showed less expression in response to prolonged hypoxic culturing compared to normoxic cultures.

Look @ the diagram again in http://www.wikipathways.org/index.php/Pathway:WP2840 . Check out 'FLRT3'(not in the diagram) and 'MSX2'(centre-right). Than look@ Dr Cotsareli's patent @ http://www.google.com/patents/US20110021599 . 'FLRT3' and 'MSX2' are the 34th and 47th most upregulated gene, respectively- in non-balding scalp(normoxic) when compared to balding scalp(hypoxic)

MSX2:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386654/

‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation
Liang Ma,1,2 Jian Liu,3 Tobey Wu,3 Maksim Plikus,3 Ting-Xin Jiang,3 Qun Bi,2 Yi-Hsin Liu,4 Sven Müller-Röver,5 Heiko Peters,1 John P. Sundberg,6 Rob Maxson,7 Richard L. Maas,1,* and Cheng-Ming Chuong3,*
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available free at Development
See other articles in PMC that cite the published article.
Go to:
SUMMARY
Msx2-deficient mice exhibit progressive hair loss, starting at P14 and followed by successive cycles of wavelike regrowth and loss. During the hair cycle, Msx2 deficiency shortens anagen phase, but prolongs catagen and telogen. Msx2-deficient hair shafts are structurally abnormal. Molecular analyses suggest a Bmp4/Bmp2/Msx2/Foxn1 acidic hair keratin pathway is involved. These structurally abnormal hairs are easily dislodged in catagen implying a precocious exogen. Deficiency in Msx2 helps to reveal the distinctive skin domains on the same mouse. Each domain cycles asynchronously – although hairs within each skin domain cycle in synchronized waves. Thus, the combinatorial defects in hair cycling and differentiation, together with concealed skin domains, account for the cyclic alopecia phenotype.

Keywords: Alopecia, Hair cycle, Hair differentiation, Homeobox genes, Msx2, Foxn1, Ha3, Fgf5, Mouse

FLRT3:

Flrt2 and Flrt3 have overlapping and non-overlapping expression during craniofacial development.
Gong SG1, Mai S, Chung K, Wei K.
Author information
1Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6. sg.gong@dentistry.utoronto.ca
Abstract
Craniofacial morphogenesis is a complex multi-step process that involves numerous biological processes to coordinate the growth, proliferation, migration, and subsequent differentiation of the cranial neural crest cells. Members of the Fibronectin Leucine-Rich Transmembrane (Flrt) gene family have been previously reported to be widely expressed in the developing embryo. We mapped the expression of Flrt2 and Flrt3 at critical stages of craniofacial development and found that, during early craniofacial development, Flrt2 was highly expressed initially in the cranial neural crest cells and Flrt3 in the midbrain. Later both genes were expressed in the developing pharyngeal region. Flrt2 expression predominated in the neural crest-derived mesenchyme in the medial aspect of the developing frontonasal region in close relationships with the expression of Fgfr2, Shh, and Msx1, three genes shown previously to play critical roles in craniofacial development. Flrt2 was also present in the vomero-nasal organ, mandibular primodia, and the posterior aspects of the unfused and fused secondary palatal shelves. Flrt3, however, had a more restrictive expression, being present in the mesenchyme underlying the ectoderm of the medial nasal process and in the mandibular primordium and in regions undergoing outgrowth, in a pattern that overlapped with Bmp4 expression. Both Flrt2 and Flrt3 were later found to be present at sites of epithelial-mesenchymal interactions such as the developing tooth buds, hair follicles, and eye. Together the data suggested important roles for Flrt2 and Flrt3 in mediating events such as NCC migration, chondrogenesis and epithelial-mesenchymal interactions during craniofacial development.

PAX1 is heavily expressed in the https://en.wikipedia.org/wiki/Pharyn...ch_(embryology) all the way to the cranium. our neck and skull anatomy is defined by the PAX genes.

MSX1, MSX2's family member- is the 51 most upregulated gene in non-balding scalp when compared to balding scalp @ http://www.google.com/patents/US20110021599 . It is also, just like MSX2- a BMP signalling target gene(atually, both of them are also WNT signalling's target genes) as can be seen here again http://www.wikipathways.org/index.php/Pathway:WP2840 (topleft)

[TheKingofFighters]

Finally, Hypoxia increases intracelluar calcium levels(which is why the patent i linked suggested the usage of Nifedipine- it blocks L-type calcium channels and results in vasodilation- the latter a process similar to Minoxidil)- which c-fos and inflammatory processes are heavily dependent on.

Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter.
Berna N1, Arnould T, Remacle J, Michiels C.
Author information
Abstract
Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
Copyright 2001 Wiley-Liss, Inc.

[TheKingofFighters]

Further on, look@ LGR5( centre/right) of the same diagram in http://www.wikipathways.org/index.php/Pathway:WP2840 , then look @ Dr Cotsareli's patent http://www.google.com/patents/US20110021599 - this time round on the most upregulated genes in non-balding scalp when compared to balding scalp. LGR5 is aka GPR49. It's the 9th most upregulated and a WNT target gene:

http://www.ncbi.nlm.nih.gov/pubmed/18849992

Lgr5 marks cycling, yet long-lived, hair follicle stem cells.
Jaks V1, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgård R.
Author information
Abstract
In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5(+) cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5(+) progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5(+) cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling(In the context of AGA, anything that involves hedgehog signalling, as discussed above to your previous post- involves PAX1) in maintaining the Lgr5(+) stem cell population.

Now look at this http://ethos.bl.uk/OrderDetails.do?u...l.ethos.682727

Abstract:
Leucine rich repeat containing G-protein coupled receptor 5 (LGR5) is a well-established stem cell marker in the normal intestine. Recent evidence suggests LGR5 is also a marker of cancer stem cells in colorectal tumours. Cancer stem cells propagate and maintain tumours and are hypothesized to be refractory to therapy. Solid tumours frequently experience hypoxia and an unresolved question remains as to how the cancer stem cell population survives this environmental stress. Several regulatory links are known to exist between hypoxic and stem cell signalling pathways. However, the role of hypoxia in regulating LGR5 is yet to be elucidated. Here it is reported that hypoxia down-regulates LGR5 expression. Both protein and mRNA expression is reduced in hypoxia. LGR5 down regulation was observed in cells derived from adenoma, primary carcinoma and metastases, suggesting this process occurs throughout tumourigenesis. [U]LGR5 was found to be re-expressed following re-oxygenation,[/U[(aka 'normoxia') demonstrating tumour cells ability to switch between expressing LGR5 in normoxic conditions and reducing expression in hypoxia. LGR5 is an established target gene of the WNT signalling pathway and hypoxia has been reported previously to regulate the WNT pathway. Results presented here suggest hypoxic down-regulation of the WNT pathway mediates the hypoxic regulation of LGR5. Topflash WNT reporter activity and expression of a selection of additional WNT target genes decreased in hypoxia in the cell lines tested here. Preliminary ChiP experiments suggest WNT signalling effectors Beta-catenin and TCF4 are lost from the LGR5 promoter in hypoxia. It has been reported previously that HIF-1 interacts with the WNT pathway in hypoxia to down-regulate WNT target gene expression. However HIF-1 does not regulate LGR5 in the cell lines tested here. Highly related HIF-2, though, is critical in the hypoxic regulation of LGR5 in the LoVo cell line and not in other cell lines tested here. The reversible down regulation of stem cell markers during hypoxia may have important implications for targeting cancer stem cells in vivo where tumours are heterogeneous with fluctuating areas of hypoxia.

[TheKingofFighters]

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

Inbeforethecure- Give me your valuable input on this:

http://www.wikipathways.org/index.php/Pathway:WP2840

Look at 'NR3C1'(centre/south of the diagram)- that's the Gluccocorticoid receptor and it's in a direct relationship with FOS(aka c-FOS) and FOSB

Then look at this http://www.google.com/patents/US20110021599 - Dr Cotsareli's patent on the most downregulated genes in non-balding scalp when compared to balding scalp. FOS and FOSB are the 3rd and 4th most downregulated genes in non-balding scalp, respectively.

What do you think? Gluccocorticoid underexpression or overexpression in AGA? Gluccocorticoid resistance?

Bear in mind that Calcium channel blockers directly inhibits FOS because:

L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia.
Premkumar DR1, Mishra RR, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR.
Author information
Abstract
In the present study we examined the intracellular pathways that link hypoxia to activation of c-fos gene expression. Experiments were performed on rat pheocromocytoma-12 (PC-12) cells. c-fos mRNA and promoter activities were analyzed by RT-PCR and reporter gene assays, respectively. BAPTA, a Ca(2+) chelator, inhibited c-fos mRNA and promoter activation by hypoxia. Nitrendipine, an L-type Ca(2+)-channel blocker, abolished, whereas BAY K 8644, an L-type channel agonist, enhanced c-fos activation by hypoxia. Ca(2+) currents were augmented reversibly by hypoxia, suggesting that Ca(2+) influx mediated by L-type Ca(2+) channels is essential for c-fos activation by hypoxia. We next determined downstream pathways activated by intracellular Ca(2+) concentration. Immunoblot analysis revealed Ca(2+)/calmodulin-dependent kinase II (CaMKII) protein in PC-12 cells and revealed that hypoxia increased the enzyme activity. KN-93, a CaMK inhibitor, blocked CaMKII activation and c-fos promoter stimulation by hypoxia. Ectopic expression of an active mutant of CaMKII (pCaMKII290) stimulated c-fos promoter activity under normoxia. Hypoxia increased phosphorylation of CREB at the serine residue 133 (Ser-133), and KN-93 attenuated this effect. Point mutations at the Ca(2+)/cAMP-responsive cis-element (Ca/CRE) attenuated, whereas point mutations in the serum-responsive cis-element (SRE) abolished transcriptional activation of c-fos by hypoxia. These results demonstrate that c-fos activation by hypoxia involves CaMK activation and CREB phosphorylation at Ser-133 and requires Ca/CRE and SRE. These observations demonstrate that Ca(2+)-dependent signaling pathways play a crucial role in induction of c-fos gene expression, which may underlie long-term adaptive responses to hypoxia.

http://www.ncbi.nlm.nih.gov/pubmed/10797155

1 interesting to take note of is that weight gain(though not that severe when compared to GC agonists) is a common side effect of CCBs- and this is a hallmark of GC agonists as well(like betamethasone). I can attest this because i am experimenting with https://en.wikipedia.org/wiki/Nifedipine now in accordance with this old patent http://www.google.com/patents/US5407944 that discovered the balding scalp is chronically and significantly hypoxic when compared to non-balding scalp.

While i do not agree with it's premise that suggested the usage of E2(Beta-estradiol) for hair growth(because of the huge tremendous sides that i've been through)- it makes sense that that the balding scalp is hypoxic, which translate to a localised form peripheral hypertension, as I can feel this chronic tightness on my head.

[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.

[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]

[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]

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]

Atually, the possible cure- is in our vomit

[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.

[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

[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.

[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.