پایان نامه بیوشیمی بالینی -175 صفحه
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پایان نامه بیوشیمی بالینی - بررسی شناسایی مارکرهای حیاتی جدید، در سرطان پستان زنان با روش پروتئومیکس
A Survey on the Identification of New Vital Markers in Breast Cancer in Women by Proteomics
قیمت انجام پایان نامه از 100 هزار تومان تا 4 میلیون تومان متغیر است که پایان نامه های آماده قیمت ناچیزی دارند.
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چکیده
سرطان پستان دومین سرطان شایع در دنیا است که در سالهای اخیر با استفاده از تستهای غربالگری و هورمون درمانی و شیمی درمانی تا حدودی کنترل شده است. اما عود مجدد بیماری بعد از درمان و یا متاستاز ممکن است منجر به مرگ شود. در انواع مختلف این بیماری، بیان یکسری ایزوفرمهای اختصاصی رسپتورهای هورمونی ویا رسپتورهای سطح سلول دچار تغییرات می شوند(1-2).
شناسایی پروتئینهای دخیل در این بدخیمی، میتواند به عنوان اهداف تشخیصی و یا درمانی حائز اهمیت باشد. از آنجایی که بدخیمیها میتوانند به دلایل متعددی بروز نمایند برآن شدیم تا با بررسی الگوی بیان پروتئینها درسرطان پستان، پروتئینهایی را که به صورت متفاوت دربافت سرطانی پستان بیان میگردند، مورد شناسایی قرار دهیم.
آنالیز پروتئوم به کمک الکتروفورز دو بعدی (2D-Gel) انجام میشود. هدف ما از این تحقیق بررسی الگوی تغییرات پروتئینها در فرآیند تبدیل شدن بافت سالم به بافت سرطانی بوسیله انجام عملیات آزمایشگاهی شامل: استخراج بافتی (عصاره گیری)، تفکیک توسط الکتروفورز، مرئیسازی، جداسازی و بالآخره شناسایی پروتئینهای بافتی است.
روش کار: در این تحقیق ازبافت سالم و توموری پستان، مربوط به سه نفر كه طی عمل جراحی در بیمارستان امید مشهد انجام شده بود، استفاده گردید. این مطالعه به گونهای طراحی شده است که در ابتدا به وسیله تکنیک الکتروفورز دو بعدی، و سپس رنگآمیزی با کوماسی بریلیانت بلو، پروتئینهای بافتی، به صورت لکههای تقریباً آبی رنگ بر روی ژل ظاهر شده که الگویی خاص از پروتئینهای موجود دربافت سالم دریک ژل و همچنین الگوی پروتئینهای بافت سرطانی در یک ژل دیگر را ارائه داده که پس از عکسبرداری توسط نرمافزار ImageMaster، مقایسه میشوند. توسط همین نرم افزار میزان افزایش بیان تمامی لكهها نیز محاسبه گردید. سپس لکههای توصیه شده توسط نرم افزار، به دقت جدا شده و بر طبق هماهنگی به عمل آمده، به مرکز تحقیقات ژنوم در دانشگاه انگلستان، ارسال شدند. پروتئینها، پس از هضم داخل ژلی به وسیله تریپسین، با استفاده از دستگاه MALDI-TOF/TOFو نرم افزار، MASCOT، شناسایی شدند. توضیح اینكه در مجموع از هر یك از سوپرناتانتهای سالم و توموری تعداد 6 ژل، ودر كل تعداد 12ژل با كیفیت مطلوب تهیه شد.
یافتهها: پاسخ ارسالی درمورد نتایج شناسایی كلهها از انگلستان، نشان دهنده تعیین هویت 6 پروتئین بود، که به ترتیب عبارتند از: (KRT8: کراتین، نوع II اسکلت سلولی) با افزایش بیان 6./6 ، (UBXN10: ایزوفرمی تک رشتهای مشابه یوبی کوئیتین10) با افزایش بیان 16/6، (PRDX6: Peroxiredoxin6) با افزایش بیان 47/2، (KRT19: کراتین نوع 1 اسکلت سلولی) با افزایش بیان 24/10، (GSTP-1: گلوتاتیون S- ترانسفراز پی– 1) با افزایش بیان 37/3 و (TRPM1: تروپومیوزین با زنجیره و TRPM2: تروپومیوزین با زنجیره ) با افزایش بیان 5/2 بودند. این پروتئینها توسط سایت Panther Classification system و بر اساس نقش آنها در فرآیندهای بیولوژیکی در سلول در 5 کلاس طبقهبندی شدند، که شامل: فعالیت کالتیکی و فرآیندهای متابولیکی (TPM1,TPM2,PRDX6) و اجزاء حیاتی یا اورگانیکی سلولها و پروتئینهای پیوندی (UBXN10, KRT19, KRT8, TPM1, TPM2)، فرآیند توسعه (KRT19, KRT8, TPM1, TPM2) و همچنین فعالیت آنتیاکسیدانی (PRDX6) می گردیدند. شواهد نشان میدهد که مهمترین مسیرهای سلولی در ایجاد سرطان پستان بر اساس اهمیت، عبارتند از: مسیرTGF-β1 و فسفریلاسیون MAPK14. در این مطالعه تمامی پروتئینها افزایش بیان را نشان دادند.
کلمات کلیدی: سرطان پستان، پروتئومیکس، بیومارکر، الکتروفورز دو بعدی، پروتئومیکس، طیف سنجی جرمی
فهرست مطالب:
مقدمه
هدف کلی:
اهداف ویژه:
اهداف كاربردی:
سوالات تحقیق:
فرضیه های تحقیق:
ﻓﺼﻞ اول: کلیات موضوع
1-1- بیان مسئله:
(1-1-1) شناسایی خصوصیات بافت پستان
(1-1-2) تعریف کلی سرطان
(1-1-3) سرطان:
(1-1-4) ﺗﻐﯿﯿﺮات ﮐﻠﯽ ژﻧﺘﯿﮑﯽ در اﻧﻮاع ﺳﺮﻃﺎنﻫﺎ
(1-1-5) شیوع سرطان ها درجهان
(1-1-6) ﺳﺮﻃﺎن پستان
(1-1-7) مهمترین عوامل خطر درابتلاء به سرطان پستان:
(1-1-8) ﻣﻄﺎﻟﻌﺎت ژﻧﺘﯿﮏ ﻣﻮﻟﮑﻮﻟﯽ در ﺳﺮﻃﺎن پستان
(1-1-8-1)PCNA:
(1-1-8-2) Ki67:
(1-1-8-3) ERو PR
(1-1-8-4) P53:
(1-1-8-5) ﮔﯿﺮﻧﺪه ﻋﺎﻣﻞ رﺷﺪ اﭘﯿﺪرﻣﯽ HER-2/neu
(1-1-8-6): Myc2; Nird; Niard; bHLHe39; AU016757: یا (c-Myc)
(1-1-8-7) Bcl-2:
(1-1-8-8)D1 سیکلین:
(1-1-8-9) BRCA-1 وBRCA-2:
(1-1-8-10) ژنهای ترمیم کننده DNA:
(1-1-8-11) رﯾﺰ RNA ﻫﺎ:
(1-2) ﺑﯿﻮﻣﺎرﮐﺮ
(1-2-1) ﺗﻌﺮﯾﻒ ﺑﯿﻮﻣﺎرﮐﺮ یا ماركر حیاتی
(1-2-2) راهﻫﺎی ﺷﻨﺎﺧﺖ ﺑﯿﻮﻣﺎرﮐﺮﻫﺎ
(1-3) ﭘﺮوﺗﺌﻮﻣﯿﮑﺲ
(1-3-1) کاربردهای پروتئومیکس در مطالعه سرطان
(1-4) اﻟﮑﺘﺮوﻓﻮرز دو ﺑﻌﺪی 2D))
فصل دوم: بررسی متون
(2 – 1) تاریخچه پروتئومیکس:
فصل سوم: روش انجام کارآزمایشگاهی
(3-1) مشخصات مواد مورد استفاده در این پایان نامه:
(3-2) مشخصات وسایل و دستگاه های مورد استفاده
(3-3) نوع بافت مورد استفاده:
(3-4) روش انجام کارهای آزمایشگاهی :
(3-4-1) تهیه معرفها:
(3-4-2) تهیه بافر هموژن کننده بافت (Rehydration):
(3-4-3) هموژن كردن بافت (لیز سلولی)
(3-4-3-1) نحوه اندازه گیری وتعیین محتوای پروتئینی به روش بردفورد:
(3-4-4) انجام الکتروفورز دو بعدی
(3-4-4-1) مرحله اول الکتروفورز دو بعدی :IEF انجام بعد اول
(3-4-4-1-1) تهیه نمونه پروتئینی دستگاه:
(3-4-4-1-2) مرحله ری هیدراسیون (Rehydration)
(3-4-4-1-3) مرحله ایزو الکتریک فوکوسینگ IEF :
(3-4-4-1-4) مرحله متعادل سازی بین بعدهای الکتروفورز
(3-4-4-2) انجام مرحله دوم الکتروفورز (SDS-PAGE):
(3-4-4-2-1) ساخت بافرها و آماده نمودن تانک الکتروفورز
(3-4-4-2-1-1)- بافر تعادلی: 8/8 =pH
(3-4-4-2-1-2) تهیه رانینگ بافر8-5/8= pH :
(3-4-4-2-2(آماده نمودن دستگاه الکتروفورز:
(3-4-4-2-2-1) تهیه ژل بخش پایینی، ژل آکریلامید
(3-4-4-2-2-2) نحوه ی قرارگیری نوار IPG بر روی ژل
(3-4-4-2-2-3) تهیه بخش بالایی، ژل آگارز
(3-4-4-2-2-4)انجام الکتروفورز:
(3-5) رنگ آمیزی پروتئین ها
(3-6) آنالیز لکه های پروتئینی با استفاده از نرم افزار
(3-7) بریدن نقاط پروتئینی از روی ژل
(3-8) شناسائی پروتئین ها:
(3-9) تجزیه و تحلیل داده های موجود در بانک های اطلاعاتی
(3-10) طبقه بندی پروتئین ها
(3-11) روش آماری
بخش چهارم: نتایج وبحث
نتایج
(4-1) ﺑﺮرﺳﯽ
(4-2) ﻧﻤﻮدار ﻣﺮﺑﻮط ﺑﻪ ﺗﻘﺴﯿﻢ ﺑﻨﺪی ﭘﺮوﺗﺌﯿﻦ ﻫﺎ ﺗﻮﺳﻂ ﺳﺎﯾﺖ Panther Classification System
(4-3) ﺑﺤﺚ ﺑﺮ روی ﻧﺘﺎﯾﺞ
(4-3-1) کراتینها (Keratin)
الف - Keratin, type I cytoskeletal) انسانی با شماره دسترسی P08727 (K1C19)*
ب - Keratin, type II cytoskeletal) انسانی با شماره دسترسی P05787 (K2C8_HUMAN) وکراتین نوع دو
ج- UBXN10- یوبی کوئیتین (Ubiquitin) با شماره دسترسی Q96LJ8
د- گلوتاتیون s- ترانسفراز (GST) با شماره دسترسی P09211
هـ - (6PRDX) Peroxiredoxin -6 با شماره دسترسی P30041
ز- Tropomyosin beta chain and Tropomyosin alpha-1 chain تروپومیوزین (TRM1-TRM2) با شماره دسترسی های P09493 وP079521
ﭘﯿﺸﻨﻬﺎدﻫﺎ:
ضمیمه جدول ها تهیه بافرها
مآخذ و منابع
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Pilot Reseach for discovery of Biomarkers in women breast cancer, by proteomics in mashhad city
Cancer is a complicated disease the identification of the biomarkers of which for early diagnosis of the disease, classification of different kinds of tumors, and finding treatment objectives may help in curing it. Although, the genes involved in different kinds of cancers have been identified extensively but the protein changes in cells during the cancer progress has not been fully recognized.
The ever-increasing need for recognizing the nature, procedure, and functional method of the product of genes, i.e., proteins, has led to the emergence of proteomics. Proteomics studies the protein content or proteome of a cell, a tissue, or physiologic fluid in developmental and environmental conditions and/or specific pathology. Separation, exposure, and identification of the characteristics of the complicated compounds containing thousands of proteins are measures taken in the study of proteome. Proteomics methods used for specific identification of cancer markers (tumors) may be the compliments of gene analysis methods. Employing proteomics technique give a great deal of help in identifying proteins involved in this process. Proteomics is a protein analysis system for their identification and quantitation.
Breast cancer is the second prevalent cancer in the world which has been nearly controlled in the recent years by employing screening tests, hormone therapy, and chemotherapy. But the recurrence of the disease after treatment or metastasis may lead to death. In different kinds of this disease, the expression of a series of specific isoforms of hormone receptors or the receptors of the cell surface change. (2-1).
The identification of the proteins involved in this malignancy can be important as the diagnostic or treating objectives. Since malignancies may emerge due to different causes, therefore, we decided to study the expression pattern of proteins in breast cancer and identify the proteins which are expressed different in cancerous tissue of breast.
Proteome analysis is done by 2D Electrophoresis (2D-Gel). Our objective in this research is studying the pattern of protein changes in the process of transforming a healthy tissue to a cancerous one by conducting experimental operations such as tissue extraction, differentiation by electrophoresis, visibility, separation, and finally, identification of tissue proteins.
Work procedure: The present study has been designed in such a way that, at first, number of patterns tissue proteins are appeared on gel in blue stains by 2-D Electrophoresis technique and staining with Coomassie brilliant blue which presents a special pattern from the proteins existing in healthy tissue in a gel as well as the pattern of the proteins of cancerous tissue in another gel. They are compared with each other after taking photos by ImageMaster software. Then, the stains recommended by the software were separated carefully and sent to the Research Center of Genome at England University. The proteins digested inside gel by Trypsin were identified by using MALDI-TOF/TOF and MASCOT software.
Conclusions:The results sent back from England: According to the results sent back by the university the following six proteins were identified: (Keratin 8: Type II cytoskeletal), (UBXN10: a single peptide match to UBX domain-containing protein 10), (Keratin19: type I cytoskeletal) (PRDX6: Peroxiredoxin-6), (GSTP1:Glutathione S-transferase P), (TPM1:Tropomyosin beta chain and TPM2: Tropomyosin alpha I chain). The above proteins were classified into 5 classes by Classification System Panther site on the basis of their role in cellular process contain: catalytic activity and metabolic process (TPM1,TPM2, PRDX6), cellular component organization or biogenesis and protein binding (UBXN10, KRT19, KRT8, TPM1, TPM2), developmental process(KRT19,KRT8, TPM1,TPM2), and also some antioxidant activity (PRDX6). Evidences shows the most important passways in breast cancer by importance are, TGF-β1 and MAPK14 phophorilation.
In this study, all proteins were increased.
Keywords: breast cancer, proteomics, biomarkers, two-dimensional electrophoresis, proteomics, mass spectrometry