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Cilvēka 14.Hromosomas Proteasomu Gēnu Polimorfismu Saistība Ar Metaboliskām Un Autoimūnām Slimībām

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Cilvēka 14.Hromosomas Proteasomu Gēnu Polimorfismu Saistība Ar Metaboliskām Un Autoimūnām Slimībām Latvijas Universit āte Medic īnas fakult āte Cilv ēka 14.hromosomas proteasomu gēnu polimorfismu saist ība ar metabolisk ām un autoim ūnām slim ībām PROMOCIJAS DARBS Darba autors: Ilva Trapi Ħa (dzimusi Poudžiunas) stud. apl. Nr.: Dokt06004 Darba vad ītājs: Dr.habil.biol, prof. Nikolajs Sjakste Recenzenti: Dr.med. Gustavs Latkovskis Dr. med. Rita Lugovska Prof. Elza Husnutdinova RĪGA, 2010 SATURS KOPSAVILKUMS..........................................................................................................................6 SUMMARY ....................................................................................................................................7 IEVADS ..........................................................................................................................................8 1. LITERAT ŪRAS APSKATS ...................................................................................................11 1.1. 2. TIPA CUKURA DIAB ĒTS ...................................................................................................11 1.1.1. Slim ības pato ăen ēze un izplat ība .............................................................................11 1.1.2. 2.tipa cukura diab ēta molekul ārā ăen ētika ...............................................................12 1.2. JUVEN ĪLAIS IDIOP ĀTISKAIS ARTR ĪTS ................................................................................16 1.2.1. Slim ības pato ăen ēze un izplat ība .............................................................................16 1.2.2. JIA molekul ārā ăen ētika: asoci āciju mekl ējumi.......................................................18 1.3. CILV ĒKA GENOMA 14. HROMOSOMA ...............................................................................22 1.4. PROTEASOMAS ..................................................................................................................25 1.4.1. Proteasomu visp ārīgais apraksts...............................................................................25 1.4.2. Proteasomas aktivatori..............................................................................................29 1.4.3. Proteasomu neproteol ītisk ā darb ība..........................................................................33 1.4.4. Proteasomu saist ība ar slim ībām ..............................................................................34 1.4.5. Proteasomu prote īnu g ēni cilv ēka genom ā...............................................................36 1.4.6. Proteasomu sist ēmas prote īnu g ēnu saist ība ar slim ībām.........................................39 2. MATERI ĀLI UN METODIKA ..............................................................................................43 2.1. DNS PARAUGU KOLEKCIJA ...............................................................................................43 2.2. DNS IZDAL ĪŠANA UN KONCENTR ĀCIJAS NOTEIKŠANA ....................................................45 2.3. ANALIZ ĒTIE LOKUSI UN TO GENOTIP ĒŠANAS METODES ..................................................46 2.3.1. Mikrosatel ītu anal īze ................................................................................................47 2.3.2. SNP anal īze ..............................................................................................................52 2.4. MAR ĖIERU FUNKCIONALIT ĀTES BIOINFORM ĀTISK Ā ANAL ĪZE .......................................57 2.4.1. Polimorfismu sekvences izmai Ħu ietekme uz DNS un RNS sekund āraj ām strukt ūrām..............................................................................................................................57 2.4.2. Polimorfismu saitu sekvences izmai Ħu ietekme uz DNS liekumiem.......................58 2.4.3. Polimorfismu saitu saist ība ar transkripcijas faktoriem un to modifik ācija atkar ībā no sekvences izmai Ħā m ...........................................................................................58 2.4.4. Polimorfismu saitu sekvences izmai Ħu ietekme uz mikroRNS piesaisti un/vai veidošanos .............................................................................................................................59 2.4.5. Polimorfismu saitu sekvences ietekme uz matricas RNS veidošanos......................59 2 2.5. DATU APSTR ĀDE UN STATISTISK Ā ANAL ĪZE .....................................................................59 3. REZULT ĀTI ...........................................................................................................................62 3.1. 14 Q HROMOSOMAS POLIMORFISMI ...................................................................................62 3.1.1. 14q13 re ăiona mikrosatel ītu izp ēte...........................................................................62 3.1.2. 14q proteasomu prote īnu g ēnu SNP anal īze un atlase..............................................64 3.2. 2. TIPA CUKURA DIAB ĒTA ASOCI ĀCIJAS ANAL ĪZE ............................................................66 3.2.1. Lokusa 14q13 HSMS mar ėieru asoci ācijas anal īze ar T2DM .................................67 3.2.2. SNP asoci ācijas anal īze ar T2DM ............................................................................71 3.3. JUVEN ĪLĀ IDIOP ĀTISK Ā ARTR ĪTA ASOCI ĀCIJAS ANAL ĪZE ................................................74 3.3.1. Lokusa 14q13 HSMS mar ėieru asoci ācijas anal īze ar JIA.......................................74 3.3.2. SNP asoci ācijas anal īze saist ībā ar JIA ....................................................................80 3.4. IESP ĒJAMO FUNKCIJU BIOINFORM ĀTISK Ā ANAL ĪZE POLIMORFISMIEM SAIST ĪTIEM AR JIA UN T2DM..........................................................................................................................84 3.4.1. HSMS mar ėieri.........................................................................................................84 3.4.2. Viena nukleot īda polimorfismi.................................................................................88 4. DISKUSIJA.............................................................................................................................92 4.1. 14 Q HROMOSOMAS POLIMORFISMI ...................................................................................92 4.1.1. 14q13 re ăiona MS polimorfismi un to variabilit āte .................................................92 4.1.2. 14q proteasomu prote īnu g ēnu SNP .........................................................................93 4.2. 2. TIPA CUKURA DIAB ĒTA ASOCI ĀCIJAS ANAL ĪZE .............................................................94 4.2.1. Lokusa 14q13 saist ība ar T2DM ..............................................................................94 4.2.2. 14q proteasomu prote īnu g ēnu saist ība ar T2DM ....................................................96 4.3. JUVEN ĪLĀ IDIOP ĀTISK Ā ARTR ĪTA ASOCI ĀCIJAS ANAL ĪZE ................................................97 4.3.1. Lokusa 14q13 saist ība ar JIA....................................................................................97 4.3.2. 14q proteasomu prote īnu g ēnu saist ība ar JIA .......................................................100 4.4. AR SLIM ĪBĀM ASOCI ĒTO POLIMORFISMU IESP ĒJAMĀ FUNKCION ĀLĀ NOZ ĪME.............103 4.4.1. HSMS mar ėieru iesp ējam ā funkion ālā noz īme......................................................103 4.4.2. SNP mar ėieru iesp ējam ā funkion ālā noz īme..........................................................105 4.5. REZULT ĀTU KOPSAVILKUMS ..........................................................................................107 SECIN ĀJUMI .............................................................................................................................108 IZMANTOT Ā LITERAT ŪRA ...................................................................................................111 PUBLIK ĀCIJAS UN PREZENT ĀCIJAS ..................................................................................133 PATEIC ĪBA ................................................................................................................................138 PIELIKUMI.................................................................................................................................140 3 SAĪSIN ĀJUMI 14ch – 14.hromosoma 14q – 14.hromosomas garais plecs 3’UTR – G ēna 3’ netransl ējam ā da Ĝa 5’UTR – G ēna 5’ netransl ējam ā da Ĝa 95% CI – Konfidences interv āls ( confidence intervals ) pie 95% ANA – Antinukle ārās antivielas ATF – Adenoz īntrifosf āts BMC – Latvijas Biomedic īnas p ētījumu un studiju centrs BMI – Ėerme Ħa svara indekss ( body mass index ) bp – B āzu p āris cDNS – Kod ējoš ā dezoksiribonukle īnsk ābe del – Del ēcija DNS – Dezoksiribonukle īnsk ābe HapMap – Starptautisks projekts cilv ēka genoma haplotipu kartes izveidošanai (hapmap.ncbi.nlm.nih.gov/ ) HLA – Cilv ēka leikoc ītu antig ēns ( Human leukocyte antigen ) HSMS – Mikrosatel ītu nosaukums „Human Salaspils Microsatellites” ins – Insercija JIA – Juven īlais idiop ātiskais artr īts JIoA – Juven īlais idiop ātiskais oligoartr īts JIpA – Juven īlais idiop ātiskais poliartr īts kDa – Kilodaltons LMP2 – Liela mutifunkcion ālā peptid āze 7 (apz īmēts ar ī ar PSMB8) LMP7 – Liela mutifunkcion ālā peptid āze 2 (apz īmēts ar ī ar PSMB9) MAF – Ret ās al ēles frekvence ( minor allele frequency) MALDI-TOF MS – Polimorfismu genotip ēšanas metode ar MALDI-TOF masas spektrometru MECL-1 – Multikatal ītisk ā endopeptid āzes kompleksa subvien ība (apz īmēts
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