Primary Genetic Reasons Why We Bald - Pax1/Foxa2, Dr. Cotsarelis Scoliosis study and More...

I was researching a bit on MPB earlier and came across a thread that was very interesting, i wanted to bring it up on the Immortal forum to see what you guys think about viewing MPB at this angle. The Scoliosis Study and Dr. Cotsarelis patent are very interesting and it puts everything into prospective on what is happening in the balding scalp. I will take out some posts from the thread that i found to be the most interesting and hopefully Cs can and other members contribute their thoughts on this.

Below i will list the 5 most up-regulated genes in the haired/non-balding scalp from the Scoliosis Study and how to up-regulate them for the balding scalp.

GPRC5D <= Ultra low dose topical Tretinoin(0.0005% )

CDT6<= Topical Calcitriol/Calcipotriol

LY6G6D<= ?

S100A3<= Topical Calcitriol/Calcipotriol

COMP<= Topical Calcitriol/Calcipotriol, topical Valproic acid

Here are 5 of the most down-regulated genes in the haired/non-balding scalp

-CCL19<= Topical Calcitriol/Calcipotriol

-FOSB<= Topical Valproic acid

-c-FOS<= Topical Valproic acid, Topical/oral Verapamil, topical D609

-PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant

-CORIN<=

Three endpoint genes indicated by Dr. Cotsarelis that are significantly up-regulated in the haired scalp.

CD34<== Topical Valproic acid

CD200<== Topical Cacitirol/Calcipotriol

Intergrin A6<= Ultra low dose topical Tretinoin(0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6 with the other being the Parathyroid hormone-related protein(not a small molecule)

Accoriding to Dr Cotsarelis's patent, CD200's expression is significantly downregulated in bald-scalp.
"Preservation of hair follicle stem cells in AGA.

"The preservation of KRT15hiITGA6hi cells in AGA is consistent with the current clinical concept that AGA is a nonscarring type of alopecia. Dermatologists classify alopecias into scarring and nonscarring categories. Some types of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, and graft-versus-host disease) are associated with destruction of hair follicle stem cells in the bulge and permanent hair loss. Ablation of the stem cell compartment leading to scarring alopecia has been replicated experimentally in mice through transgene expression of a cytotoxic gene in the bulge (2). In reversible types of alopecia (e.g., alopecia areata), inflammation targets hair follicle progenitor cells but spares hair follicle stem cells. In these disorders, regrowth occurs with suppression of inflammation and subsequent regeneration of the hair follicle from uninjured stem cells (5). Our finding that AGA, in the clinical category of nonscarring alopecia, demonstrated preservation of hair follicle stem cells suggests potential reversibility of this condition."

This is also interesting because i remember when CS said in a pod cast that inflammation is the primary cause of AGA, however, that is just a basic understanding of it and there are many other factors below it.

Basically CD34 + CD200 + CD49f = Hair Growth

"looking back at Cotsarelis findings of the gene differences in haired-scalp, we can see that the gene CORIN is the most under-regulated gene even lower than PTGDS- enzyme for synthesising PGD2 which is surprising.
Whatever the mechanism is, there is for certain, a modified function of the genes implicated in this section of the pathway that is a major cause of AGA- because they influence how downstream pathways behave- including but not limited to WNT/signalling pathway like DKK1, BMP-signalling like BMP-2, TGF Beta signalling like TGF Beta 1, TH1/Th2 cytokines ratio and activity, intracellular calcium levels, etc, etc"

It seems like Calcitirol or Calcipotriol actually take care of a lot of the genes associated with balding by either down regulating or up regulating them, i think the treatment is a derivative of Vitamin D and its hard to find.Topical applications WILL go systemic- but they will affect hair follicles the balding scalp first before some of it goes into the bloodstream and affect the balding skull to enhance bone resorption.

"one potential downside(if any) i can envision from this protocol(Topical Calcitirol+ Leukotriene Antagonists like Singulair aka Montelukast + Crth2 blocker like TM/Seti/Rama?OC)- would be that we might be more susceptible to fungal infections and common ailments like flu, etc- because we are basically weakening our immune system. That is why we want to limit as much of the de-immunising effects to the balding scalp for as much as possible"
If we are taking natural supplements like the immortal line, the immune suppressing side effect might be balanced with these natural supplements an keep everything in check, but that needs to be looked into.

Something CS also talked about -This seems to fit the theory of those who preach that AGA is atually a condition induced by bacteria on the scalp: http://en.wikipedia.org/wiki/Cathelicidin

Vitamin D
"It can be hoped that the public health significance of undiagnosed VD hyopvitaminosis(suggesting that pathology of AGA could be due to a lack of Cacitirol-activated Cacitirol Receptor levels on the balding scalp) will be finally recognized first by the medical community then by society in general(It might be- Multiple ethinc groups living north of the Equator has a lack of vitamin D levels in their body- not to mention that Vitamin D was only originally classed as a vitamin(the name of it already tells us so) before being reclassed as a critical nuclear hormone that has diverse fucntions in the human body- particularly Calcium homeostasis and the Immune system. Coupled with the fact that the Pax1 gene is in charge of sclerotome planning of the spine and skull, and is also expressed on the adult human scalp- there remains the possibility that variants in the region of the Pax1/foxa2 locus is influencing VDR's function(atually it is indeed doing so by altering VDR's 'binding site'- as indicated by the Scoliosis study)- localized to the balding scalp and skull) Hopefully more and more lay people will understand that VD deficiency is a risk factor of many diseases affecting broad segments of society just as the lack of vitamin C, certain minerals, unhealthy nutrition and so on are detrimental. In an ideal scenario, complaint-free people will be regularly screened not only for hypertension, diabetes and various types of cancer but also for VD hypovitaminosis. Epidemiologists might provide more data on that which factors of living conditions and eating habits contribute to VD hypovitaminosis, which has already reached epidemic proportions."

Off topic a bit but when i read this i was shocked because this is exactly what happened to me. When Cs and i skyped, he mentioned the atlas vertebra. When i was a kid and to this day i cannot stop twisting my neck and i try to stop, i get this burning sensation in my neck and it forces me to crack and twist it around to feel comfortable. I wonder if this has anything to do with it.

https://upload.wikimedia.org/wikipedia/commons/d/d4/C1_lateral.png

The position of the Atlas influences the entire body

"In a chain-reaction process, a misalignment of the Atlas may cause asymmetries of the entire skeleton, such as one shoulder being higher than the other with pain in the scapula, scoliosis, tilted pelvis with consequent danger of herniated discs (discopathy), pain in the back, hips, knees and even feet.

As long as postural defects exist, permanent muscular tension develop which, as well as being painful, can cause other vertebrae in the column to become blocked (subluxations).

The resulting subluxations may create persistent compression on certain nerve roots. More and more frequently doctors use cortisone against those irritations, which is indeed a useful medicament, but which causes severe, well noted side effects in the long term.

Compression of certain nerves (leads to pins and needles) in arms and legs, while the pressure put on other nerves leads to malfunctions in the corresponding organs. This gives rise to a series of disturbances, even in apparently unrelated areas of the body.

Enlarged, hardened muscles as a result of constant tension compress lymphatic structures as well as the arteries and veins which run between these muscles. This leads to decreased blood flow and a build-up of metabolic waste products in the tissue. This condition causes a vicious circle, making the muscles even more rigid.

Certainly, there are other factors to be taken into account which can affect a symmetrical, upright posture of the body. However, misalignment of the Atlas can be absolutely decisive. Experience has shown that in many cases - after a simple correction of the Atlas - the skeleton consequently takes on a more correct and natural shape.

If one shoulder is higher than the other or the pelvis is tilted, complaints are inevitable, sooner or later.

everything is true. that's what i have been complaining about the lymph nodes below my jawline and under my ears for a longtime."
I would also get that sound in my ear, it goes "EEEEEEEE" and i get that everyday. This gene has something to do with it
H6 family homeobox 2 <====Inner ear and vestibular function (altered gene by the Pax1/Foxa2 AGA/Scoliosis haplotype variant)

My nose is always stuffed no matter what as well, maybe there is a connection with all these symptoms i listed above and the Atlas Vertebra with MPB. Let me know if you guys are experiencing anything similar.


Malformations in the Atlas verterba could be the origin of AGA. (where Lymphocytes are carried in)

https://upload.wikimedia.org/wikipedia/commons/f/f3/Michael_Jordan_-_Parietal_eminence.png

A thorough examination of the entire Vertebral column, especially the Atlas verterba(top of the spine) by a Neurosurgeon could even reveal some results. A correction allignment of the Atlas verterba could even potentially 'cure' AGA by decompressing blood vessels, lymphatic vessels and nerves that transport growth factors, carries away lymphatic drainage includingwaste products and restoring ganglion cells functionality to the balding scalp and balding skull.

Interesting because S. Foote theory is based on that as well.

Anytime i am outside, i observe other balding individuals and their heads have something underneath the skin that is protruding out, you can usually see it in the front from the middle of the forehead going up. Its puffy and looks like a big bruise, check out some photos online and you will know what i am talking about.

Back to hair growth:

CD200(upregulated by calcitriol) +CD49F aka Intergrin A6(upregulated by Tretinoin) reexpression

"was sufficient to reconstitute a whole follicle"- Dr Cotsarelis.

As well as adding a PGD2 inhibitor and other things, that is the reason why SwissTemples regrew his temples, he used exactly that.

"Our findings indicate that small molecules that activate the Wnt/?-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth. "

Valproic Acid Promotes Hair Re-Growth and Induces Terminally Differentiated Hair Markers

"Valproic Acid Promotes Hair Growth in Cutaneous Wounds in Mice"

"CORIN was the 1 changing the pro-hair growth form of 1-32 BNP to the other form 4-32 BNP.

Until it was noticed that Cotsarelis patent indicated it as the most downregulated gene in haired-scalp(even more than PTGDS- the enzyme for making PGD2)

I i doubt it's not because of a lack of efficacy. Rather there could be a lack of FURIN in bald scalp Coupled with the overexpression of CORIN

this means FURIN is rendering T cells to be more lax in its activity against the hair follicles on the scalp- and some AGA mechansims must be lowering its expression on the balding scalp AND regulating CORIn's expression instead"
Might be more important than PGD2, definitely has to be down-regulated to achieve growth.

Here is what the the entire regrowth regimen would look like, its like a semi cure.
1)topical calcipotriol or calcitriol.

Primary rationale: it induces the expression of CD200.

"Expression of CD200 and Integrin A6(CD49f) was sufficient to reconstitute a whole follicle"- Dr Cotsarellis

2)IF it indeed posseses ability to perform those functions relevant to multiple pathsays in regards to hair growth to what has been indicated for it on paper- then topical Valproic acid would be the next best thing(Gsk3. inhibitor, Androgen receptor inhibitor, FosB and c-fos inhibitor via inhibting PKC, CD34 expression inducer, HDAC2 inhibitor, Foxp1 activator, etc)

Primary rationale: It induces CD34 expres​sion(PGE2 does so too).

3)topical tretinoin in an ultra low dose(0.0005%) upregulates Foxp1, GPRC5D, RAR and most importantly- Integrin A6

Primary rationale: It induces Integrin A6 expres​sion( I could find only tretinoin and Parathyroid hormone-related protein(not a small molecule) that does so.

All the unregulated genes in the haired scalp (not balding)

"Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data.

Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth.

Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B).

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==GPR49 forms a complex with LPR6(which DKK1 inhibits). DKK1 is inhibited by WAY262611, Magnesium L-threonate, Magnesium L ascorbyl 2 phosphate and Valproic acid.

The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular.<==Calcipotriol/Calcitriol

GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E).<===Ultra low dose Tretinoin(0.0005%-0.005%)

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G).
<== The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth."

The Final Protocol would consist of something like this.

1)CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%- nothing higher than that)
2)CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%- nothing higher than that)
3)CD49f: topical Tretinoin (generic creams/gels are available at 0.01%- nothing higher than that)
4)An Androgen Receptor blocker(preferably topical) like RU58841 or Valproic acid, etc. Stops further hair growth-inhibiting androgenic actions in AGA scalps.

to provide the basics to regrow hair

AND

5)optional 1.5mm once/mth soft dermarolling protocol(Just do till the scalp turns slightly red. It is absolutely unnecessary to whip things up into a bloody mess- literally).

6) Setipiprant: Blocking PGD2

I think adding PGE2 powder like siwsstemples did would also benefit a ton.

So i want to know what you guys think of all this, it might be our only way to achieve actual real hair growth on bald scalps.
I will not be giving all this a try anytime soon because i know some of these chemicals are dangerous, i will look for the topical Calcitirol or Calcipotriol as well as Valproic acid, lithium chloride, Setipiprant and topical PGE2 and that is what i am willing to try for regrowth.

All these findings were from Dr. Cotsarelis and the Scoliosis study and it gives us an idea on the things that are going on during AGA. They used people with full heads of hair and people who are balding and as you can tell, a lot of genes were either up regulated and down regulated.

I will post the link of where this post was discussed -https://www.baldtruthtalk.com/threads/21255-Pax1-Foxa2-1-of-the-primary-genetic-reasons-why-we-balding-men-are-balding

Thank You

Wow, I remember a guy on HLT being ridiculed for using tretinoin

Thank you, Yaro.

SoloDomo wrote:Wow, I remember a guy on HLT being ridiculed for using tretinoin

Yeah that stuff is dangerous, and i definitely will not be going near that. This post was just to get an idea of what exactly is going on during AGA, with everything we know now from Dr. Cotsarelis i think we can regrow a full head of hair.

Finding safer ways to up regulate or down regulate the genes involved in AGA and take care of the other factors in the safest way possible is what we need to figure out now.

CF wrote:Thank you, Yaro.

Yeah no problem.

Yeah about number 5, I watched something where the guy was showing how he DRs, and says you just need to get it red, not make yourself bleed profusely (actually not bleed at all).

I'm doing cd's bottle DT method though, obviously that's not invasive like DR, so I can do it every day like he recommends.

Going to start internal castor oil too.

YARO wrote:

SoloDomo wrote:Wow, I remember a guy on HLT being ridiculed for using tretinoin

Yeah that stuff is dangerous, and i definitely will not be going near that. This post was just to get an idea of what exactly is going on during AGA, with everything we know now from Dr. Cotsarelis i think we can regrow a full head of hair.

Finding safer ways to up regulate or down regulate the genes involved in AGA and take care of the other factors in the safest way possible is what we need to figure out now.

Thank you for this. I have scoliosis (<20 degrees) and this was really interesting. What is your background YARO. You seem very knowledgeable in the subject

johndoe1225 wrote:Yeah about number 5, I watched something where the guy was showing how he DRs, and says you just need to get it red, not make yourself bleed profusely (actually not bleed at all).

I'm doing cd's bottle DT method though, obviously that's not invasive like DR, so I can do it every day like he recommends.

Going to start internal castor oil too.

Well i usually like to make my scalp bleed when i do DR, if your only making the scalp red then the needles are not penetrating the skin.

I have never tried DT and probably never will, i remember somewhere on Immortals home page where CS actually wrote about doing message therapy and said its not really worth if i remember correctly, but don't quote me on that. They did a study on it and all it did was make the hairs thicker but didn't grow any new hair which is what we are after.

A few thoughts....

Tretinoin is really an analog form of vitamin A, that is more powerful (which means side-effects).

I always prefer to go the natural route. Enough of the proper vitamin A, ala all-trans-retinoic acid (retinol) balances out the anti-microbial peptides (cathelicidins) from vitamin D.

There are many types of structural malformations (sometimes iatrogenic/caused by a medical person) that can affect gene regulation in MPB.

CausticSymmetry wrote:A few thoughts....

Tretinoin is really an analog form of vitamin A, that is more powerful (which means side-effects).

I always prefer to go the natural route. Enough of the proper vitamin A, ala all-trans-retinoic acid (retinol) balances out the anti-microbial peptides (cathelicidins) from vitamin D.

There are many types of structural malformations (sometimes iatrogenic/caused by a medical person) that can affect gene regulation in MPB.

CS, I believe ATRA (also known as retinoic acid, or the medical name Tretinoin) is the active form of vitamin A in the skin. I believe the body will convert retinyl esters (the most common form of vitamin A in animals, although eating animal products will also deliver some retinol) into retinol, which the body will convert into other forms of vitamin A, including ATRA.

sorry for being annoying recently but i find this fascinating, my uncle started balding at and he had a long history of scoliosis...

Ok in laymen terms what foods and supplements should we take to upregulate these genes to regrow hair possibly?