Gene Symbol: Adra1a
Description: adrenergic receptor, alpha 1a
Alias: Adra1c, alpha-1A adrenergic receptor, alpha-1A adrenoceptor, alpha-1A adrenoreceptor, alpha-1C adrenergic receptor
Species: mouse
Products:     Adra1a

Top Publications

  1. Gray K, Short J, Ventura S. The alpha1A-adrenoceptor gene is required for the alpha1L-adrenoceptor-mediated response in isolated preparations of the mouse prostate. Br J Pharmacol. 2008;155:103-9 pubmed publisher
    ..This implies that alpha1L-adrenoceptors are indeed a functional phenotype of alpha1A-adrenoceptor. ..
  2. Serfas M, Tyner A. HNF-1 alpha and HNF-1 beta expression in mouse intestinal crypts. Am J Physiol. 1993;265:G506-13 pubmed
    ..Although HNF-1 is necessary for transcription of the AFP gene, other factors must be involved in eliciting the cell type-specific pattern of AFP expression in the intestine...
  3. Vinge L, von Lueder T, Aasum E, Qvigstad E, Gravning J, How O, et al. Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 Uncovers Distinct Functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness. J Biol Chem. 2008;283:10601-10 pubmed publisher
    ..The reduced tolerance to elevation of preload may cause impaired ability to withstand pathophysiological mechanisms of heart failure. ..
  4. Bergaya S, Faure S, Baudrie V, Rio M, Escoubet B, Bonnin P, et al. WNK1 regulates vasoconstriction and blood pressure response to ? 1-adrenergic stimulation in mice. Hypertension. 2011;58:439-45 pubmed publisher
  5. Wu S, Dahl E, Wright C, Cypher A, Healy C, O Connell T. Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” a1-AR signaling pathway. J Am Heart Assoc. 2014;3:e000145 pubmed
    ..Importantly, these data help resolve the discrepancy between nuclear localization of a1-ARs and a1-AR-mediated physiologic function. ..
  6. Huang Y, Wright C, Merkwan C, Baye N, Liang Q, Simpson P, et al. An alpha1A-adrenergic-extracellular signal-regulated kinase survival signaling pathway in cardiac myocytes. Circulation. 2007;115:763-72 pubmed
    ..Absence of the alpha1A-ERK pathway can explain the failure to activate ERK after aortic constriction in alpha1ABKO mice and can contribute to the development of apoptosis, dilated cardiomyopathy, and death. ..
  7. Charalambous M, Ferron S, da Rocha S, Murray A, Rowland T, Ito M, et al. Imprinted gene dosage is critical for the transition to independent life. Cell Metab. 2012;15:209-21 pubmed publisher
    ..This shows that appropriate dosage control at imprinted loci can act as a critical determinant in postnatal survival during phases of physiological adaptation. ..
  8. Cheng Z, Zhu Q, Dee R, Opheim Z, Mack C, Cyr D, et al. Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth. J Biol Chem. 2017;292:2065-2079 pubmed publisher
    ..This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux. ..
  9. McElligott Z, Winder D. Alpha1-adrenergic receptor-induced heterosynaptic long-term depression in the bed nucleus of the stria terminalis is disrupted in mouse models of affective disorders. Neuropsychopharmacology. 2008;33:2313-23 pubmed
    ..Thus a loss of this plasticity at glutamatergic synapses in BNST could contribute to affective behavioral phenotypes of these mice. ..

More Information


  1. Doze V, Handel E, Jensen K, Darsie B, Luger E, Haselton J, et al. alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse. Brain Res. 2009;1285:148-57 pubmed publisher
    ..These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression. ..
  2. Docherty J. Subtypes of functional alpha1-adrenoceptor. Cell Mol Life Sci. 2010;67:405-17 pubmed publisher
    ..Central actions are now being elucidated. ..
  3. Ross S, Rorabaugh B, Chalothorn D, Yun J, Gonzalez Cabrera P, McCune D, et al. The alpha(1B)-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model. Cardiovasc Res. 2003;60:598-607 pubmed
    ..These results suggest that the alpha(1B)-AR does not have a major role in the positive inotropic response in the mouse myocardium but may negatively modulate the response of the alpha(1A)-AR. ..
  4. Ennis R, Asico L, Armando I, Yang J, Feranil J, Jurgens J, et al. Dopamine D₁-like receptors regulate the α₁A-adrenergic receptor in human renal proximal tubule cells and D₁-like dopamine receptor knockout mice. Am J Physiol Renal Physiol. 2014;307:F1238-48 pubmed publisher
    ..Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems. ..
  5. Shi T, Papay R, Perez D. α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake. J Recept Signal Transduct Res. 2016;36:261-70 pubmed publisher
  6. Gericke A, Kordasz M, Steege A, Sanbe A, Goloborodko E, Vetter J, et al. Functional role of ?1-adrenoceptor subtypes in murine ophthalmic arteries. Invest Ophthalmol Vis Sci. 2011;52:4795-9 pubmed publisher
    ..These findings provide evidence that the ?(1A)-AR subtype mediates adrenergic vasoconstriction in murine ophthalmic arteries. ..
  7. Rokosh D, Simpson P. Knockout of the alpha 1A/C-adrenergic receptor subtype: the alpha 1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc Natl Acad Sci U S A. 2002;99:9474-9 pubmed
    ..We conclude that the alpha 1A/C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. alpha 1A/C-selective antagonists might be desirable antihypertensive agents. ..
  8. Gupta M, Papay R, Jurgens C, Gaivin R, Shi T, Doze V, et al. alpha1-Adrenergic receptors regulate neurogenesis and gliogenesis. Mol Pharmacol. 2009;76:314-26 pubmed publisher
    ..Our results indicate that alpha(1)-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases. ..
  9. Rockman H, Koch W, Lefkowitz R. Cardiac function in genetically engineered mice with altered adrenergic receptor signaling. Am J Physiol. 1997;272:H1553-9 pubmed
    ..The purpose of this review is to summarize current knowledge about the regulation of cardiovascular homeostasis involving signaling pathways through stimulation of adrenergic receptors...
  10. O Connell T, Rokosh D, Simpson P. Cloning and characterization of the mouse alpha1C/A-adrenergic receptor gene and analysis of an alpha1C promoter in cardiac myocytes: role of an MCAT element that binds transcriptional enhancer factor-1 (TEF-1). Mol Pharmacol. 2001;59:1225-34 pubmed
    ..However, the mouse alpha1C gene was not transcribed in the neonatal heart and was not activated by alpha1-AR and other hypertrophic agonists in rat myocytes, and thus differed from other MCAT-dependent genes and the rat alpha1C gene. ..
  11. Montgomery M, Chan T, Swigart P, Myagmar B, Dash R, Simpson P. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice. PLoS ONE. 2017;12:e0168409 pubmed publisher
  12. Niedermair T, Kuhn V, Doranehgard F, Stange R, Wieskötter B, Beckmann J, et al. Absence of substance P and the sympathetic nervous system impact on bone structure and chondrocyte differentiation in an adult model of endochondral ossification. Matrix Biol. 2014;38:22-35 pubmed publisher
    ..We propose that sensory and sympathetic neurotransmitters have crucial trophic effects which are essential for proper bone formation in addition to their classical neurological actions. ..
  13. Alonso Llamazares A, Zamanillo D, Casanova E, Ovalle S, Calvo P, Chinchetru M. Molecular cloning of alpha 1d-adrenergic receptor and tissue distribution of three alpha 1-adrenergic receptor subtypes in mouse. J Neurochem. 1995;65:2387-92 pubmed
    ..The alpha 1a subtype is also expressed in many tissues, whereas the alpha 1b subtype has a more restricted expression, with high levels in striatum, brainstem, and diencephalus. ..
  14. Yeh C, Fan Y, Xu Y, Yang Y, Simpson P, Mann M. Shift toward greater pathologic post-myocardial infarction remodeling with loss of the adaptive hypertrophic signaling of alpha1 adrenergic receptors in mice. PLoS ONE. 2017;12:e0188471 pubmed publisher
  15. Turnbull L, McCloskey D, O Connell T, Simpson P, Baker A. Alpha 1-adrenergic receptor responses in alpha 1AB-AR knockout mouse hearts suggest the presence of alpha 1D-AR. Am J Physiol Heart Circ Physiol. 2003;284:H1104-9 pubmed
    ..Furthermore, alpha(1)-AR inotropic responses depend critically on the experimental conditions. ..
  16. Zhang H, Cotecchia S, Thomas S, Tanoue A, Tsujimoto G, Faber J. Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling. Am J Physiol Heart Circ Physiol. 2004;287:H2106-14 pubmed
    ..These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury. ..
  17. O Connell T, Swigart P, Rodrigo M, Ishizaka S, Joho S, Turnbull L, et al. Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload. J Clin Invest. 2006;116:1005-15 pubmed
    ..studied cardiac pressure overload in mice with double KO of the 2 main alpha1-AR subtypes in the heart, alpha 1A (Adra1a) and alpha 1B (Adra1b)...
  18. Doze V, Papay R, Goldenstein B, Gupta M, Collette K, Nelson B, et al. Long-term ?1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Mol Pharmacol. 2011;80:747-58 pubmed publisher
    ..This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders. ..
  19. Alexandre E, de Oliveira M, Campos R, Kiguti L, Calmasini F, Silva F, et al. How important is the ?1-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of ?1-adrenoceptor to urethral contractility. Am J Physiol Renal Physiol. 2017;312:F1026-F1034 pubmed publisher
    ..The differential expression of ?1-adrenoceptors in the proximal urethra may contribute to the higher incidence of urinary incontinence in women and obstructed voiding in men. ..
  20. Lin F, Owens W, Chen S, Stevens M, Kesteven S, Arthur J, et al. Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy. Circ Res. 2001;89:343-50 pubmed
    ..To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR. ..
  21. Stone E, Lin Y, Sarfraz Y, Quartermain D. Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha1-adrenoceptors by a full agonist. Brain Res. 2009;1291:21-31 pubmed publisher
    ..It is hypothesized that the alpha(1)-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors. ..
  22. Cikos S, Rehák P, Czikková S, Veselá J, Koppel J. Expression of adrenergic receptors in mouse preimplantation embryos and ovulated oocytes. Reproduction. 2007;133:1139-47 pubmed
  23. O Connell T, Ishizaka S, Nakamura A, Swigart P, Rodrigo M, Simpson G, et al. The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse. J Clin Invest. 2003;111:1783-91 pubmed
    ..Thus, alpha(1)-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress. ..
  24. Chen Y, Palczewska G, Masuho I, Gao S, Jin H, Dong Z, et al. Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. Sci Signal. 2016;9:ra74 pubmed publisher
    ..D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, respectively...
  25. Tanaka Y, Funabiki M, Michikawa H, Koike K. Effects of aging on alpha1-adrenoceptor mechanisms in the isolated mouse aortic preparation. J Smooth Muscle Res. 2006;42:131-8 pubmed
  26. Telegdy G, Schally A. Involvement of neurotransmitters in the action of growth hormone-releasing hormone antagonist on passive avoidance learning. Behav Brain Res. 2012;233:326-30 pubmed publisher
    ..The results demonstrate that the muscarinic acetylcholine receptor, the 5-HT1/5-HT2 serotonergic receptor and opioid receptors are involved as mediators in the action of MZ-4-71 on the consolidation of passive avoidance learning. ..
  27. Mustafa S, See H, Seeber R, Armstrong S, White C, Ventura S, et al. Identification and profiling of novel ?1A-adrenoceptor-CXC chemokine receptor 2 heteromer. J Biol Chem. 2012;287:12952-65 pubmed publisher
    ..This has important implications for the use and future development of pharmaceuticals targeting these receptors...
  28. Cowley P, Wang G, Joshi S, Swigart P, Lovett D, Simpson P, et al. ?1A-Subtype adrenergic agonist therapy for the failing right ventricle. Am J Physiol Heart Circ Physiol. 2017;313:H1109-H1118 pubmed publisher
    ..Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the ?1A-subtype is a therapeutic target to treat RV failure. ..
  29. Huang Y, Wright C, Kobayashi S, Healy C, Elgethun M, Cypher A, et al. GATA4 is a survival factor in adult cardiac myocytes but is not required for alpha1A-adrenergic receptor survival signaling. Am J Physiol Heart Circ Physiol. 2008;295:H699-707 pubmed publisher
    ..This also identifies an important mechanistic difference in alpha1-signaling between adult and neonatal cardiac myocytes. ..
  30. Chaulet H, Lin F, Guo J, Owens W, Michalicek J, Kesteven S, et al. Sustained augmentation of cardiac alpha1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes. J Mol Cell Cardiol. 2006;40:540-52 pubmed
    ..To our knowledge this is the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling. ..
  31. Billaud M, Lohman A, Straub A, Looft Wilson R, Johnstone S, Araj C, et al. Pannexin1 regulates ?1-adrenergic receptor- mediated vasoconstriction. Circ Res. 2011;109:80-5 pubmed publisher
    ..Our data demonstrate for the first time a key role for Panx1 in resistance arteries by contributing to the coordination of vascular smooth muscle cell constriction and possibly to the regulation of blood pressure. ..
  32. Wakabayashi C, Kiyama Y, Kunugi H, Manabe T, Iwakura Y. Age-dependent regulation of depression-like behaviors through modulation of adrenergic receptor ??A subtype expression revealed by the analysis of interleukin-1 receptor antagonist knockout mice. Neuroscience. 2011;192:475-84 pubmed publisher
  33. Cowley P, Wang G, Chang A, Makwana O, Swigart P, Lovett D, et al. The α1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am J Physiol Heart Circ Physiol. 2015;309:H888-96 pubmed publisher
    ..In conclusion, upregulation of α1-AR inotropy in failing RV myocardium requires the α1A-subtype and is opposed by the α1B-subtype. The α1A subtype might be a therapeutic target to improve the function of the failing RV. ..
  34. Kordasz M, Manicam C, Steege A, Goloborodko E, Amato C, Laspas P, et al. Role of α₁-adrenoceptor subtypes in pupil dilation studied with gene-targeted mice. Invest Ophthalmol Vis Sci. 2014;55:8295-301 pubmed publisher
    ..The lack of a single α₁-AR subtype does not appear to cause atrophy in the mouse iris. ..
  35. Xiao L, Scofield M, Jeffries W. Molecular cloning, expression and characterization of cDNA encoding a mouse alpha1a-adrenoceptor. Br J Pharmacol. 1998;124:213-21 pubmed
    ..This response to NA could be reversed by pretreatment of the transfected cells with prazosin. 5. Based on the above evidence, we concluded that the cloned cDNA is that of the mouse alpha1a-adrenoceptor. ..
  36. White C, Choong Y, Short J, Exintaris B, Malone D, Allen A, et al. Male contraception via simultaneous knockout of ?1A-adrenoceptors and P2X1-purinoceptors in mice. Proc Natl Acad Sci U S A. 2013;110:20825-30 pubmed publisher
  37. Ogata T, Ueyama T, Isodono K, Tagawa M, Takehara N, Kawashima T, et al. MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. Mol Cell Biol. 2008;28:3424-36 pubmed publisher
    ..These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias. ..
  38. Rorabaugh B, Gaivin R, Papay R, Shi T, Simpson P, Perez D. Both alpha(1A)- and alpha(1B)-adrenergic receptors crosstalk to down regulate beta(1)-ARs in mouse heart: coupling to differential PTX-sensitive pathways. J Mol Cell Cardiol. 2005;39:777-84 pubmed
    ..However, alpha(1)-AR subtypes are coupled to different beta-AR mediated signaling pathways with the alpha(1B)-AR being pertussis toxin sensitive. ..
  39. Michelotti G, Bauman M, Smith M, Schwinn D. Cloning and characterization of the rat alpha 1a-adrenergic receptor gene promoter. Demonstration of cell specificity and regulation by hypoxia. J Biol Chem. 2003;278:8693-705 pubmed
    ..These findings for the alpha(1a) gene should facilitate elucidation of alpha(1)AR-mediated mechanisms involved in distinct myocardial pathologies. ..
  40. Daly C, Ross R, Whyte J, Henstridge C, Irving A, McGrath J. Fluorescent ligand binding reveals heterogeneous distribution of adrenoceptors and 'cannabinoid-like' receptors in small arteries. Br J Pharmacol. 2010;159:787-96 pubmed publisher
  41. Martínez Salas S, Campos Peralta J, Pares Hipolito J, Gallardo Ortiz I, Ibarra M, Villalobos Molina R. Alpha1A-adrenoceptors predominate in the control of blood pressure in mouse mesenteric vascular bed. Auton Autacoid Pharmacol. 2007;27:137-42 pubmed
    ..6 The results indicate that the isolated mouse mesenteric vascular bed expresses alpha1A-adrenoceptors and suggest a very discrete role for 1B-adrenoceptors. ..
  42. Zimnik N, Treadway T, Smith R, Araneda R. ?(1A)-Adrenergic regulation of inhibition in the olfactory bulb. J Physiol. 2013;591:1631-43 pubmed publisher
    ..Furthermore, the general ?2-AR agonist clonidine (10 ?M) failed to affect sIPSC frequency. Thus, the NA-mediated increase in GCMC inhibition in the OB results mostly from activation of the ?1A-AR subtype. ..
  43. Sanbe A, Tanaka Y, Fujiwara Y, Tsumura H, Yamauchi J, Cotecchia S, et al. Alpha1-adrenoceptors are required for normal male sexual function. Br J Pharmacol. 2007;152:332-40 pubmed
    ..These results demonstrate that alpha(1)-adrenoceptors, particularly alpha(1A)-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility. ..
  44. Pulinilkunnil T, He H, Kong D, Asakura K, Peroni O, Lee A, et al. Adrenergic regulation of AMP-activated protein kinase in brown adipose tissue in vivo. J Biol Chem. 2011;286:8798-809 pubmed publisher
    ..Furthermore, AMPK ? Ser(485/491) phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects. ..
  45. Hosoda C, Hiroyama M, Sanbe A, Birumachi J, Kitamura T, Cotecchia S, et al. Blockade of both alpha1A- and alpha1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery. Am J Physiol Heart Circ Physiol. 2007;293:H514-9 pubmed
    ..These results suggest that lack of both alpha(1A)- and alpha(1B)-ARs could be necessary to inhibit neointimal formation in the mouse femoral artery. ..
  46. Tsutsumi R, Fukata Y, Noritake J, Iwanaga T, Perez F, Fukata M. Identification of G protein alpha subunit-palmitoylating enzyme. Mol Cell Biol. 2009;29:435-47 pubmed publisher
    ..Together, our findings revealed that DHHC3 and DHHC7 regulate GPCR-mediated signal transduction by controlling Galpha localization to the plasma membrane. ..
  47. Lin Y, Quartermain D, Dunn A, Weinshenker D, Stone E. Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation. Synapse. 2008;62:516-23 pubmed publisher
    ..These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings. ..
  48. McCloskey D, Turnbull L, Swigart P, O Connell T, Simpson P, Baker A. Abnormal myocardial contraction in alpha(1A)- and alpha(1B)-adrenoceptor double-knockout mice. J Mol Cell Cardiol. 2003;35:1207-16 pubmed
  49. Telegdy G, Schally A. Neurotransmitter-mediated action of an antagonist of growth hormone-releasing hormone on anxiolysis in mice. Behav Brain Res. 2012;233:232-6 pubmed publisher
  50. Wright C, Wu S, Dahl E, Sazama A, O Connell T. Nuclear localization drives ?1-adrenergic receptor oligomerization and signaling in cardiac myocytes. Cell Signal. 2012;24:794-802 pubmed publisher
    ..In summary, our data indicate that ?1-AR nuclear localization can drive the formation of receptor oligomers and regulate signaling in adult cardiac myocytes. ..
  51. Kobayashi S, Tomiyama Y, Hoyano Y, Yamazaki Y, Kusama H, Itoh Y, et al. Gene expressions and mechanical functions of ?1-adrenoceptor subtypes in mouse ureter. World J Urol. 2009;27:775-80 pubmed publisher
  52. Wright C, Chen Q, Baye N, Huang Y, Healy C, Kasinathan S, et al. Nuclear alpha1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes. Circ Res. 2008;103:992-1000 pubmed publisher
    ..In summary, our results show that nuclear alpha1-ARs transduce signals to caveolae at the plasma membrane in cardiac myocytes. ..
  53. Anderson T, Schneider A, Barrie J, Klugmann M, McCulloch M, Kirkham D, et al. Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. J Comp Neurol. 1998;394:506-19 pubmed
    ..We conclude that abnormal expression of an oligodendrocyte-specific gene can cause axonal damage, a finding that is relevant to the pathogenesis of PLP-associated disorders and probably to other myelin-related diseases. ..