Investigation of the Effects of Retinoids and Vitamin D Derivatives on YAP1-Mediated Scar Formation

Project no. 32635 · Status: Kapanmış (Yayın bekleniyor) · 2024

Summary

<p>Wound&nbsp;healing,&nbsp;defined&nbsp;as&nbsp;the&nbsp;process&nbsp;of&nbsp;repairing&nbsp;damaged&nbsp;skin&nbsp;or&nbsp;tissues,&nbsp;consists&nbsp;of&nbsp;the&nbsp;phases&nbsp;of&nbsp;hemostasis,&nbsp;inflammation,&nbsp;proliferation,&nbsp;and&nbsp;remodeling.&nbsp;Hemostasis&nbsp;begins&nbsp;immediately&nbsp;after&nbsp;injury&nbsp;and&nbsp;functions&nbsp;to&nbsp;stop&nbsp;bleeding.&nbsp;During&nbsp;the&nbsp;inflammation&nbsp;phase,&nbsp;immune&nbsp;cells&nbsp;accumulate&nbsp;at&nbsp;the&nbsp;wound&nbsp;site.&nbsp;In&nbsp;the&nbsp;proliferation&nbsp;phase,&nbsp;the&nbsp;formation&nbsp;of&nbsp;new&nbsp;tissues&nbsp;begins.&nbsp;Fibroblasts&nbsp;produce&nbsp;collagen,&nbsp;and&nbsp;the&nbsp;formation&nbsp;of&nbsp;new&nbsp;blood&nbsp;vessels&nbsp;(angiogenesis)&nbsp;occurs.&nbsp;A&nbsp;temporary&nbsp;tissue&nbsp;called&nbsp;granulation&nbsp;tissue&nbsp;covers&nbsp;the&nbsp;wound&nbsp;surface.&nbsp;Epithelial&nbsp;cells&nbsp;start&nbsp;from&nbsp;the&nbsp;edges&nbsp;of&nbsp;the&nbsp;wound&nbsp;and&nbsp;form&nbsp;a&nbsp;new&nbsp;layer&nbsp;of&nbsp;skin.&nbsp;During&nbsp;this&nbsp;phase,&nbsp;the&nbsp;wound&nbsp;begins&nbsp;to&nbsp;contract&nbsp;and&nbsp;gain&nbsp;strength.&nbsp;In&nbsp;the&nbsp;remodeling&nbsp;phase,&nbsp;collagen&nbsp;fibers&nbsp;are&nbsp;reorganized,&nbsp;and&nbsp;the&nbsp;wound&nbsp;tissue&nbsp;becomes&nbsp;stronger&nbsp;and&nbsp;more&nbsp;flexible.</p><p>YAP1&nbsp;(Yes-Associated&nbsp;Protein&nbsp;1)&nbsp;is&nbsp;an&nbsp;important&nbsp;signaling&nbsp;pathway&nbsp;that&nbsp;enables&nbsp;cells&nbsp;to&nbsp;respond&nbsp;to&nbsp;mechanical&nbsp;and&nbsp;biochemical&nbsp;signals.&nbsp;It&nbsp;is&nbsp;regulated&nbsp;by&nbsp;the&nbsp;Hippo&nbsp;signaling&nbsp;pathway&nbsp;and&nbsp;controls&nbsp;processes&nbsp;such&nbsp;as&nbsp;cell&nbsp;growth,&nbsp;apoptosis,&nbsp;and&nbsp;tissue&nbsp;homeostasis.&nbsp;In&nbsp;its&nbsp;inactive&nbsp;form,&nbsp;YAP1&nbsp;is&nbsp;located&nbsp;in&nbsp;the&nbsp;cytoplasm&nbsp;of&nbsp;the&nbsp;cell,&nbsp;and&nbsp;when&nbsp;the&nbsp;Hippo&nbsp;pathway&nbsp;is&nbsp;active,&nbsp;it&nbsp;becomes&nbsp;phosphorylated&nbsp;and&nbsp;remains&nbsp;inactive.&nbsp;During&nbsp;wound&nbsp;healing,&nbsp;when&nbsp;YAP1&nbsp;becomes&nbsp;active,&nbsp;it&nbsp;translocates&nbsp;to&nbsp;the&nbsp;nucleus&nbsp;and&nbsp;regulates&nbsp;gene&nbsp;expression.&nbsp;This&nbsp;regulation&nbsp;promotes&nbsp;cell&nbsp;proliferation&nbsp;and&nbsp;tissue&nbsp;repair.&nbsp;YAP1&nbsp;enhances&nbsp;fibroblast&nbsp;activity,&nbsp;supporting&nbsp;collagen&nbsp;production&nbsp;and&nbsp;the&nbsp;fibrogenic&nbsp;response.&nbsp;It&nbsp;also&nbsp;contributes&nbsp;to&nbsp;angiogenesis,&nbsp;enabling&nbsp;the&nbsp;formation&nbsp;of&nbsp;new&nbsp;blood&nbsp;vessels.&nbsp;Due&nbsp;to&nbsp;these&nbsp;properties,&nbsp;the&nbsp;YAP1&nbsp;pathway&nbsp;helps&nbsp;wound&nbsp;healing&nbsp;progress&nbsp;effectively&nbsp;and&nbsp;plays&nbsp;an&nbsp;important&nbsp;role&nbsp;in&nbsp;optimizing&nbsp;tissue&nbsp;repair.</p><p>This&nbsp;study&nbsp;aims&nbsp;to&nbsp;investigate&nbsp;in&nbsp;detail&nbsp;the&nbsp;relationship&nbsp;between&nbsp;the&nbsp;YAP1&nbsp;pathway&nbsp;and&nbsp;scar&nbsp;formation&nbsp;using&nbsp;tretinoin&nbsp;and&nbsp;calcitriol,&nbsp;which&nbsp;are&nbsp;derivatives&nbsp;of&nbsp;retinoids&nbsp;and&nbsp;vitamin&nbsp;D.&nbsp;Tretinoin&nbsp;and&nbsp;calcitriol&nbsp;are&nbsp;two&nbsp;important&nbsp;topical&nbsp;agents&nbsp;frequently&nbsp;used&nbsp;in&nbsp;dermatological&nbsp;clinical&nbsp;practice.&nbsp;Tretinoin&nbsp;is&nbsp;particularly&nbsp;known&nbsp;for&nbsp;its&nbsp;effectiveness&nbsp;in&nbsp;the&nbsp;treatment&nbsp;of&nbsp;acne&nbsp;vulgaris,&nbsp;whereas&nbsp;calcitriol&nbsp;is&nbsp;commonly&nbsp;preferred&nbsp;for&nbsp;the&nbsp;treatment&nbsp;of&nbsp;inflammatory&nbsp;skin&nbsp;diseases&nbsp;such&nbsp;as&nbsp;psoriasis.&nbsp;Both&nbsp;agents&nbsp;exert&nbsp;their&nbsp;effects&nbsp;through&nbsp;different&nbsp;mechanisms.&nbsp;Tretinoin&nbsp;is&nbsp;a&nbsp;retinoid&nbsp;derivative&nbsp;and&nbsp;the&nbsp;active&nbsp;form&nbsp;of&nbsp;vitamin&nbsp;A&nbsp;acid.&nbsp;It&nbsp;works&nbsp;by&nbsp;binding&nbsp;to&nbsp;retinoic&nbsp;acid&nbsp;receptors&nbsp;(RAR)&nbsp;in&nbsp;the&nbsp;cell&nbsp;nucleus.&nbsp;Through&nbsp;these&nbsp;receptors,&nbsp;tretinoin&nbsp;regulates&nbsp;the&nbsp;differentiation&nbsp;and&nbsp;proliferation&nbsp;of&nbsp;skin&nbsp;cells&nbsp;(keratinocytes).&nbsp;Calcitriol&nbsp;works&nbsp;by&nbsp;binding&nbsp;to&nbsp;vitamin&nbsp;D&nbsp;receptors&nbsp;(VDR)&nbsp;present&nbsp;in&nbsp;skin&nbsp;cells.&nbsp;By&nbsp;interacting&nbsp;with&nbsp;these&nbsp;receptors,&nbsp;calcitriol&nbsp;reduces&nbsp;keratinocyte&nbsp;proliferation&nbsp;and&nbsp;promotes&nbsp;their&nbsp;normal&nbsp;differentiation.&nbsp;Due&nbsp;to&nbsp;these&nbsp;properties,&nbsp;these&nbsp;topical&nbsp;agents&nbsp;play&nbsp;an&nbsp;important&nbsp;role&nbsp;in&nbsp;the&nbsp;management&nbsp;of&nbsp;various&nbsp;dermatological&nbsp;diseases.</p><p>The&nbsp;research&nbsp;will&nbsp;be&nbsp;conducted&nbsp;through&nbsp;a&nbsp;wound&nbsp;healing&nbsp;experiment&nbsp;(scratch-wound&nbsp;assay)&nbsp;using&nbsp;rat&nbsp;fibroblast&nbsp;cells.&nbsp;In&nbsp;this&nbsp;experiment,&nbsp;the&nbsp;effects&nbsp;of&nbsp;YAP1&nbsp;protein&nbsp;levels&nbsp;and&nbsp;functions&nbsp;on&nbsp;the&nbsp;wound&nbsp;healing&nbsp;process&nbsp;will&nbsp;be&nbsp;evaluated,&nbsp;particularly&nbsp;through&nbsp;important&nbsp;wound&nbsp;healing&nbsp;components&nbsp;such&nbsp;as&nbsp;MMP-1&nbsp;(matrix&nbsp;metalloproteinase),&nbsp;collagen&nbsp;type-1a,&nbsp;and&nbsp;TGF-beta&nbsp;(Transforming&nbsp;Growth&nbsp;Factor).&nbsp;Another&nbsp;important&nbsp;aspect&nbsp;of&nbsp;the&nbsp;experiment&nbsp;will&nbsp;be&nbsp;the&nbsp;investigation&nbsp;of&nbsp;the&nbsp;effects&nbsp;of&nbsp;tretinoin&nbsp;and&nbsp;calcitriol&nbsp;applications&nbsp;on&nbsp;wound&nbsp;closure&nbsp;rates&nbsp;and&nbsp;YAP1&nbsp;expression.&nbsp;This&nbsp;comparative&nbsp;analysis&nbsp;with&nbsp;the&nbsp;control&nbsp;group&nbsp;will&nbsp;reveal&nbsp;the&nbsp;interactions&nbsp;of&nbsp;these&nbsp;two&nbsp;agents&nbsp;with&nbsp;scar&nbsp;formation&nbsp;and&nbsp;the&nbsp;YAP1&nbsp;signaling&nbsp;pathway.</p><p>The&nbsp;results&nbsp;of&nbsp;this&nbsp;study&nbsp;may&nbsp;provide&nbsp;important&nbsp;insights&nbsp;into&nbsp;how&nbsp;retinoid&nbsp;and&nbsp;vitamin&nbsp;D&nbsp;derivatives&nbsp;interact&nbsp;with&nbsp;the&nbsp;YAP1&nbsp;signaling&nbsp;pathway&nbsp;during&nbsp;wound&nbsp;healing&nbsp;processes,&nbsp;thereby&nbsp;contributing&nbsp;to&nbsp;the&nbsp;development&nbsp;of&nbsp;therapeutic&nbsp;strategies&nbsp;in&nbsp;this&nbsp;field.&nbsp;A&nbsp;better&nbsp;understanding&nbsp;of&nbsp;the&nbsp;critical&nbsp;roles&nbsp;of&nbsp;YAP1&nbsp;in&nbsp;wound&nbsp;healing&nbsp;and&nbsp;tissue&nbsp;regeneration&nbsp;may&nbsp;enable&nbsp;the&nbsp;development&nbsp;of&nbsp;new&nbsp;treatment&nbsp;approaches,&nbsp;especially&nbsp;for&nbsp;conditions&nbsp;such&nbsp;as&nbsp;chronic&nbsp;wounds&nbsp;and&nbsp;scar&nbsp;formation.</p>

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