Pax1/Foxa2- 1 of the primary genetic reasons why we balding men- are balding

[eldarlmario]

back to the Cotsarelis patent:

"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."

This receptor is an adult stem cell biomarker. it formes a complex with http://en.wikipedia.org/wiki/LRP6 , which http://en.wikipedia.org/wiki/DKK1 inhibits- and we would only want this to be upregulated on the balding scalp- not skull.

[eldarlmario]

Cotsarelis's patent:

"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."

(CD34 https://en.wikipedia.org/wiki/CD34 +CD200 https://en.wikipedia.org/wiki/ CD200 + CD49F https://en.wikipedia.org/wiki/ITGA6 )==>Full Terminal Hair regrowth

so slick-bald guys should not give up hope

[eldarlmario]

Off topic for awhile. Some AGA individuals might suffer from some inner ear disorders(like chronic recurring tinnitus that goes:
"eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeee" that last several minutes- and im 1 of them):

H6 family homeobox 2<== gene altered by the pax1/Foxa2 balding haplotpye variant

Molecular (SNP) Analyses of Overlapping Hemizygous Deletions of 10q25.3 to 10qter in Four Patients: Evidence for HMX2 and HMX3 as Candidate Genes in Hearing and Vestibular Function

on http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743949/

INTRODUCTION
Deletions of chromosome 10qter were first reported by Lewandowski et al. in 1978. Subsequently, Wulfsberg et al. [1989] reported three new patients and reviewed 15 previous patients and proposed a 10qter deletion syndrome. Cytogenetically, these patients had deletions of bands 10q25 or 10q26 to the terminus, as well as interstitial deletions and translocations within this region. Additionally, both familial and de novo patients have been reported [Irving et al., 2003]. Irving et al. [2003] reported 15 new patients involving interstitial and terminal deletions of chromosome bands 10q25.2?26.3, and reviewed 17 patients from the literature, supporting wide clinical variability for deletions in this region yet common features including strabismus, facial asymmetry, prominent chin, down-slanting palpebral fissures, hypertelorism, malformed or large ears, and a thin upper lip. Kehrer-Sawatzki et al. [2005] also described the phenotype of a patient with an interstitial del(10)(q25.2q25.3?q26.11) and reviewed four previously described interstitial deletion patients involving bands 10q25.2-q26.1. Courtens et al. [2006] reported a subterminal deletion del(10)(q26.2) and reviewed the literature, describing the phenotype of subterminal deletions. Subterminal patients were noted to commonly have low birth weight, microcephaly at birth, short stature in childhood/adulthood, genital anomalies in males, and behavioral problems. Their craniofacial anomalies included broad/prominent nasal bridges, prominent nose, strabismus, thin upper lip, and fifth finger clinodactyly. Overall, there is variability in the sizes and positions of distal 10q deletions, presumably causing haploinsufficiency of many different genes in this large region and therefore contributing to significant variation in phenotype.

[eldarlmario]

ok found the possible reason for the underexpression of Ephrin A3 in balding hair follicles:

Different gene expression profile observed in dermal papilla cells related to androgenic alopecia by DNA macroarray analysis.
Midorikawa T1, Chikazawa T, Yoshino T, Takada K, Arase S.
Author information
Abstract
BACKGROUND:
Androgenic alopecia (AGA) is the most common type of baldness in men. Although etiological studies have proved that androgen is one of the causes of this symptom, the defined molecular mechanism underlying androgen-related actions remains largely unknown.

OBJECTIVES:
To clarify the difference in the gene expression profile of dermal papilla cells (DPCs) in skin affected by baldness.

METHODS:
DNA macroarray study was carried out on cultured DPCs from AGA skin comparing with DPCs from skin that is not affected by baldness.

RESULTS:
From DNA macroarray analysis, we observed that 107 of the 1185 analyzed genes had differing expression levels. A marked difference was observed in the decreased gene expression of BMP2 and ephrin A3 and up-regulated in NT-4 gene. In order to clarify the roles of BMP2 and ephrin A3 in the hair follicles, we examined the proliferation of hair follicle keratinocyte and expression of a hair acidic keratin gene. Both BMP2 and ephrin A3 raised the proliferation rate of the outer root sheath cells (ORSCs) and induced gene expression in acidic hair keratin 3-II.

CONCLUSION:
These results lead us to the hypothesis that both BMP2 and ephrin A3 function as hair growth promoting factors in the hair cycle.

http://www.ncbi.nlm.nih.gov/pubmed/15488702

Primary human CD34
hematopoietic stem and progenitor cells express
functionally active receptors of neuromediators
Ulrich Steidl, Simone Bork, Sebastian Schaub, Oliver Selbach, Janette Seres, Manuel Aivado, Thomas Schroeder,
Ulrich-Peter Rohr, Roland Fenk, Slawomir Kliszewski, Christian Maercker, Peter Neubert, Stefan R. Bornstein,
Helmut L. Haas, Guido Kobbe, Daniel G. Tenen, Rainer Haas, and Ralf Kronenwett
Recently, overlapping molecular phenotypes
of hematopoietic and neuropoietic
cells were described in mice. Here, we examined
primary human CD34
hematopoietic
stem and progenitor cells applying specialized
cDNA arrays, real-time reverse-transcriptase - polymerase
chain reaction (RTPCR),
and fluorescent-activated cell sorter
(FACS) analysis focusing on genes involved
inneurobiologicfunctions.Wefoundexpression
of vesicle fusion and motility genes,
ligand- and voltage-gated ion channels, receptorkinasesandphosphatases,and,most
interestingly, mRNA as well as protein expression
of G protein - coupled receptors of
neuromediators(corticotropin-releasinghormone
1 [CRH 1] and CRH 2 receptors, orexin/
hypocretin 1 and 2 receptors, GABAB receptor,
adenosine A2B receptor, opioid 1 and
1 receptors, and 5-HT 1F receptor). As
shown by 2-color immunofluorescence, the
protein expression of these receptors was
higher in the more immature CD38dim than in
the CD38bright subset within the CD34
population,
and completely absent in fully differentiated
blood cells, suggesting that those
receptors play a role in developmentally
early CD34
stem and progenitor cells. The
intracellular concentration of cyclic adenosine
monophosphate (cAMP) in CD34
cells
was diminished significantly upon stimulation
of either CRH or orexin receptors, indicating
that those are functionally active and
coupled to inhibitory G proteins in human
hematopoietic cells. In conclusion, these
findings suggest a molecular interrelation
of neuronal and hematopoietic signaling
mechanisms in humans. (Blood. 2004;104:
81-88)
© 2004 by The American Society of Hematology


http://www.bloodjournal.org/co...l.pdf?sso-checked=true

[eldarlmario]

looking back at Cotsarelis findings of the gene differences in haired-scalp, we can see that the gene CORIN is the most under-regulated gnene(even lower than PTGDS- enzyme for synthesising PGD2) http://www.google.com/patents/US20110021599 page 92

The serine protease Corin is a novel modifier of the Agouti pathway.
Enshell-Seijffers D1, Lindon C, Morgan BA.
Author information
Abstract
The hair follicle is a model system for studying epithelial-mesenchymal interactions during organogenesis. Although analysis of the epithelial contribution to these interactions has progressed rapidly, the lack of tools to manipulate gene expression in the mesenchymal component, the dermal papilla, has hampered progress towards understanding the contribution of these cells. In this work, Corin was identified in a screen to detect genes specifically expressed in the dermal papilla. It is expressed in the dermal papilla of all pelage hair follicle types from the earliest stages of their formation, but is not expressed elsewhere in the skin. Mutation of the Corin gene reveals that it is not required for morphogenesis of the hair follicle. However, analysis of the ;dirty blonde' phenotype of these mice reveals that the transmembrane protease encoded by Corin plays a critical role in specifying coat color and acts downstream of agouti gene expression as a suppressor of the agouti pathway.

This suggest it has probably got something to do with hair colojur- probably the hair greying phenomenon or the kind of faint/weak colour we see in baby hairs(miniaturized)

Also, we can see in the entire lists of gene differences that the only Bmp that appears in it- is BMP-2(upregulated in haired-scalps than bald scalps) on page 89, agreeing with the findings of the Japanese study in the post above this.

[eldarlmario]

ok- taking an angle from this study(scoliosis) and combining the information from Dr Cotsarelis own research on PGD2(from where the concept of using a CRTh2 inhibitor for AGA came from- and proven indeed accurate by others and myself through feeling the difference it made to our scalps) and Cd34/IntergrinA6/CD200(the study that lists out the differences between balding- scalp and haired scalped from the same indidivuals(s)) plus some individual studies like the korean and japanese 1s that showed how Dkk1 inhibits hair growth, how tgf beta 2 induces catagen, how bmp-2 and ephrin a3 is downregulated in balding hair follicles, etc;

I find that the findings(on genes involved, upregulated/downregulated, etc) from them:

1)The Scoliosis study
2)Dr Cotasarelis PGD2 and Cd34/IntergrinA6/CD200 studies
3)Some individual studies by others

correlates with each other rather accurately.

In other words, like i have mentioned before:

Whatever all these truckload of binding site-altered genes(caused by the disruption of a so-called "PEC7 Enhancer" at the PAX1/FOXA2 locus) are doing:

TATA
HNF4
RAR
RXRA
STAT
BATF
COMP
VDR
HDAC2
CART1
FOXA
FOXP1
GATA3
H6 family homeobox 2
IRF
PAX5
P300

is leading to this downregulation of CD34, IntergrinA6(i ommited this in the post a few pages back) and CD200 on the balding scalp + Cd200 on the balding skull(and eyebrows for me)

Coupled with the fact that i myself indeed have a natural v-shape hairline before i started receding, slightly-curved spine and frequently-occuring parotitis of my parotid glands(just below the ears) and frequently-ocurring tinittus in my ears(mentioned very early in this thread months ago before i even stumbled on the scoliosis study) plus slight tingling sensation on my scalp temple when i massaged the lymph nodes below my jawline, ears and parathyroid glands on my neck made me feel the findings from the scoliosis study are extremely accurate.

P.S I also have occasional 'twiches" in my head that felt like some nerves were being 'twisted' whenever i adjusted my jaw or moved my neck- and again, this started during puberty but i am unsure of what the cause is and if there is any link to the balding haplotype variants.

-------------------------

[eldarlmario]

PPAR receptors and their relationship with RXRA:

Pax1(-)RXRA (DOWN) => RXRA/PPAR alpha + PPAR beta/RXRA + RXRA/PPAR gamma coactivation (DOWN) => Vitamin D Receptor:



The diagram shows how individual PPARs binds with RXRA

PPAR Beta is the 'master regulator' of sebocyte profileration and differentiation. IMO, there is nothing wrong with PPAR Beta expression. But due to certain modified functions in PPAR Alpha and/or PPAR gamma via interactions with RXRA- final gene transcription thru the VDR receptor favors sebocyte differentiation at the expense of adipocyte differentiation = more sebum and less fats on the balding scalp




Whatever the mechanism is, there is for certain(atually, it's already been indicated as being the genes with their binding sites altered by the Scoliosis study- so it's not just my own opinion), 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
Calcitirol => VDR =>Vitamin D binding protein(this step can be bypassed by using topical Calcitirol directly to the scalp http://en.wikipedia.org/wiki/Vitamin_D-binding_protein ) => RXRA + RXRB(not stated as being altered in the balding haplo type) => VDR Activation => VDR target genes (VDR activation/inactivation has significant consequences on the immune system) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597838/

VDR TARGET GENES Classical VDR Targets The most striking effect of severe vitamin D defi-ciency is rickets. Rickets can also result from mutations in theCYP27B1 or theVDR gene. 1,25(OH)2D3 is essen-tial for adequate Ca2þand Pi absorption from the intes-tine and hence for bone formation [112]. Liganded VDR has been shown to induce expression of the gene encod-ing for the major Ca2þ channel in intestinal epithelial cell, transient receptor potential cation channel, subfamily V, member 6 (TRPV6), by direct binding to a VDRE at 1.2, 2.1 and 4.3 kb from the TSS [113]. The sodium-phos-phate transport protein 2B (SLC34A2) gene was also found to be induced by 1,25(OH)2D3although no VDREs have yet been identified for this gene [114]. 1,25(OH)2D3 also down-regulates the expression of the PTH gene that opposes 1,25(OH)2D3 in regulation of serum Ca2þ and Pi levels, but up-regulates the fibroblast growth factor 23 (FGF23) gene(as posted before, this unheard of FGF has atually got alot to do with the hair), whose gene product, like PTH, lowers serum Pi levels [115]. The induction of the tumor necrosis factor ligand superfamily, member 11 (TNFSF11, also called RANKL) gene by liganded VDR via multiple distant VDREs (up to 76 kb from the TSS) leads to stimulation of osteoclast precursors to fuse and form new osteoclasts, resulting in enhanced resorption of bone [116]. Thus, this study also confirms that functional VDREs can be a large distance from the target gene TSS.

[eldarlmario]

ok i know people hate staring at a huge wall of text- so here goes:

VDR Targets in Cell Cycle Regulation

The main antiproliferative effect of 1,25(OH)2D3 on cells is a cell cycle block at the G1 phase. This can be explained by changed expression of multiple cell cycle regulator genes. Among the first targets described, expression of cyclin-dependent kinase inhibitor (CDKI) genes CDKN1A (also called p21) and CDKN1B (also called p27)(upregulates cell cycle arrest genes) were found to be up-regulated by ligand treatment [117,118]. For theCDKN1A gene, a VDRE in the proximal promoter was characterized, thus estab-lishing CDKN1A as a direct 1,25(OH)2D3 target gene [119]. More recently, it has been questioned whether CDKN1A actually represents a primary or a secondary target, the latter process via up-regulation of TGF-b or IGFBP3, and whether the described VDRE is truly func-tional [120,121]. Indeed, by screening 7 kb of the CDKN1A promoter with overlapping ChIP regions, three novel regions with 1,25(OH)2D3-induced VDR enrichment were identified, two of which also bound p53 as well [80]. The functionality of these characterized 1,25(OH)2D3-responsive regions relative to CDKN1A expression was illustrated through ChIP and 3C anal-yses [25,29]. Additional CDKIs, such asCDKN2B (p15), CDKN2A (p16), CDKN2C (p18), and CDKN2D (p19), also show transcriptional response to 1,25(OH)2D3, although the CDKN2A response appears to be secondary as it can be blocked by protein synthesis inhibitors [119,122]. In addition, the genes cyclin E1 (CCNE1), cyclin D1 (CCND1), and cyclin-dependent kinase 2 (CDK2) were also found to be down-regulated by 1,25 (OH)2D3 [120].(downregulated cell cycle progression genes) It remains to be elucidated whether these effects are primary and occur via functional VDREs on regulatory regions of these genes. Another interesting 1,25(OH)2D3 target gene isCCNC. The cyclin C-CDK8 complex was found to be associated with the RNA polymerase II basal transcriptional machinery [123] and is considered to be a functional part of mediator protein complexes that are involved in gene repression [124]. The fact that the CCNC gene, being located inchromosome6q21, is deleted in a subset of acute lymphoblasticleukemias,suggeststhatitmaybeinvolved in tumorigenesis [125]. In addition,growth arrest and DNA-damage-inducible, alpha (GADD45A) and members of the IGFBP gene family also respond to 1,25(OH)2D3 [81,126]. GADD45A plays an essential role in DNA repair and GADD45 proteins displace cyclin B1 from Cdc2 and hus inhibit the formation of M phase-promoting factor that is essential for G2/M transition [127].GADD45Ahas been shown to be a direct transcriptional target of 1,25 (OH)2D3 with a functional VDRE within the fourth exon of the gene [128]. IGFBPs modulate the activity of the circulating insulin-like growth factors (IGF) I and II. The IGFBP3 gene was first discovered to be up-regulated by 1,25(OH)2D3 and contains a functional VDRE [129]. As described above, IGFBP1 and IGFBP5 are also primary 1,25(OH)2D3 target genes [81]. Another interesting primary 1,25(OH)2D3 target is the PPARD gene(PPAR Beta, 'master regulator' of sebocyte profileration and differentiation), which contains a potent DR3-type VDRE in close proximity to its TSS [130]. PPARd and VDR proteins are widely expressed and in an apparent overlap in the physiological action of the two nuclear receptors, both are involved in the regulation of cellular growth, particularly neoplasms. HighPPARDexpression in tumor seems to be positive for the prognosis of associated cancers [131]. Overall, 1,25(OH)2D3 restricts cell cycle progression in several phases via multiple and partially redundant targets on parallel pathways that when combined provide a robust antiproliferative effect.

Relative Expression of VDR Target Genes The steady state mRNA expression levels of some VDR target genes, such as that of the CYP24A1 gene, are very low in the absence of ligand, but are induced up to 1000-fold by stimulation with 1,25(OH)2D3 [36]. Most other known primary 1,25(OH)2D3 target genes, such asCCNCandCDKN1A, often show an inducibility of twofold or less after short-term treatment with 1,25 (OH)2D3 [132,133]. These latter genes, however, exhibit 10 000e100 000-fold higher(the enzyme that converts Calcitirol to its inactive metabolite- thus rendering circulating Calcitirol biologically incapable of doing anything- even though there has been a study that stated that the inactive metabolite has a still unknown receptor of its own in the bones) basal expression levels as compared to that of theCYP24A1 gene. Thus, when the relative levels are taken into account, two- to 20-fold moreCCNCandCDKN1A thanCYP24A1mRNA mole-cules are produced after induction with 1a,25(OH)2D3.

[eldarlmario]

Why only TOPICAL calcitirol or Calcipotriol should be used:

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.

Oral go both ways but we will all want the hair follciles to be affected first AND this http://en.wikipedia.org/wiki/Vitamin_D-binding_protein is a concern because the scoliosis study stated that VDR has an altered binding site- the above could potentially be the binding sit altered and it might result in calcitirol in the blood stream NOT getting transported to the hair follicles on the balding scalp and http://en.wikipedia.org/wiki/Osteoclast in the balding skull to upregulate CD200 and hence- causing the possible pathologic reason why CD200 is unexpressed in the balding scalp and balding skull.

So to be safe- topical application will be a better option because it bypasses that step and allows calcitirol(hence- CD200) to be delivered directly to the hair follices.

[eldarlmario]

1 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.

And i believe that's how our body intended it to be anyway- a more forgiving immune environment on our heads to let our hair grow in peace while protecting the rest of our entire body with upmost due diligence from invaders.