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# System prepended metadata

title: Cystic Fibrosis 生化PA @NTUMED

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Cystic Fibrosis 生化PA @NTUMED
===
## 組員
陳韻安 李承軒 柯止善 吳一宏

## PPT
[Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects](https://docs.google.com/presentation/d/1F0-6dddm4HYT7iAjDvs-EZm4Z2k_Nx5zyDnNNh_xAsA/edit?usp=sharing)

## 報告大綱
### 一. Background Information
1. **Pathologies** of CF – Symptoms and more
2. Ionic Interaction of **CFTR** in Cystic Fibrosis
3. Causes of CF - focusing on **ΔF508** mutation of CFTR and its relation with symptoms
4. **Obstacles** - outstanding questions
5. Hypothesis & **Approaches** - tackle the obstacles
### 二. Results of paper
1. Nasal Potential Difference (NPD) - curcumin-treated and untreated CF mice
2. Rectal Potential Difference (RPD) - curcumin-treated and untreated CF mice
3. Survivors and Weight Gain - curcumin-treated and untreated CF mice
4. Processing of mutation protein - on the BHK cell line
### 三. Other perspectives - doubt about curcumin
1. Unsolved Quesitons
2. Failure of Curcumin
### 四. Treatment: 2004-2007-2015-2017-future
1. SERCA pump inhibitors
2. Ivacaftor
3. Interaction of CFTR with other factors - potential drug
3.1 Elevated miR-155 → IL-8 → inflammation in CF 
3.2 PI3K/Akt/mTOR signalling pathway

### 五. Conclusion
1. Cystic Fibrosis Overall
2. CFTR as a key regulator
3. Paper report & doubt
4. Treatment and future





## Assigned Reading
* [Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects](http://science.sciencemag.org/content/304/5670/600.long)
    * [supporting material](http://science.sciencemag.org/highwire/filestream/585846/field_highwire_adjunct_files/0/Egan_SOM.pdf)
[](https://)
## 參考資料

### 學長參考的Stanford教授的CF通論
* [Human Genome, CYSTIC FIBROSIS, J. Wine 2003](https://web.stanford.edu/class/psych121/humangenome-CF.htm)

### ΔF508發生原因（生化課之後可能會教到）
* https://en.wikipedia.org/wiki/%CE%94F508
|ATC|TTT| (Ile-Phe) → |AT_|__T| → AUU (Ile)
* https://en.wikipedia.org/wiki/Deletion_(genetics)
3-nt deletion發生的原因是nucleotide flipping.

### CFTR
#### Hypothesis of CFTR in CF
##### Low Volume Hypothesis
* [Evidence for Periciliary Liquid Layer Depletion, Not Abnormal Ion Composition, in the Pathogenesis of Cystic Fibrosis Airways Disease](http://www.sciencedirect.com/science/article/pii/S0092867400817249?via%3Dihub#FIG1)
1999, 很多病理圖
##### High Salt Hypothesis & Low Volume Hypothesis
* [The genesis of cystic fibrosis lung disease](https://www.jci.org/articles/view/6222/figure/2)
1999


##### 其他
* [Cystic Fibrosis Transmembrane Conductance
Regulator (ABCC7) Structure](http://perspectivesinmedicine.cshlp.org/content/3/2/a009514.long)
@陳韻安 注意這篇結構！

* [Ion channels as targets to treat cystic fibrosis lung disease](http://www.cysticfibrosisjournal.com/article/S1569-1993(17)30917-7/fulltext)

* [The Cystic Fibrosis Transmembrane Conductance Regulator](http://www.annualreviews.org/doi/pdf/10.1146/annurev.ph.55.030193.003141)

* [Understanding how cystic fibrosis mutations disrupt CFTR function: From single molecules to animal models](http://www.sciencedirect.com/science/article/pii/S1357272514001162)
> 4. Organ-level dysfunction in CF
Mouse models of CF have contributed greatly to our understanding of the diverse physiological roles CFTR plays in different organs (for review, see Wilke et al., 2011). However, anatomical and physiological differences between humans and mice have driven the search for new animal models of CF, which culminated in the development of CFTR knockout pigs and ferrets (Rogers et al., 2008; Sun et al., 2010). Here, we highlight selectively the contribution of these new animal models to our understanding of CF pathophysiology.
4.1. Lungs
Lung disease in CF has two components: first, defective epithelial ion transport, which prevents normal mucociliary clearance, leading to the obstruction of the airways by thick, sticky mucus. Second, there is a localised failure of the host defence system in the respiratory airways leading to persistent bacterial infection (Welsh et al., 2001; Rowe et al., 2005) (Fig. 5). Like in humans with CF, the potential difference of the nasal epithelium of newborn CFTR−/− pigs was hyperpolarised, the epithelial Na+ channel (ENaC) inhibitor amiloride elicited a large potential difference depolarisation and there was no response to the cAMP agonist isoproterenol (Rogers et al., 2008). To investigate the ion transport defect in airway epithelia from CFTR−/− pigs, Chen et al. (2010) studied transepithelial Cl−, HCO3− and Na+ transport in vivo, in freshly excised epithelia and in primary cultures of differentiated airway epithelia from CFTR−/− newborn pigs. In each preparation, the authors observed defective Cl− and HCO3− transport, but no increase in Na+ absorption or reduction in airway surface liquid (ASL) depth. Of note, Chen et al. (2010) demonstrated that the increased amiloride-sensitive current characteristic of CF epithelia results from loss of CFTR Cl− conductance, not enhanced ENaC-mediated Na+ transport.

* [CFTR structure and cystic fibrosis](http://www.sciencedirect.com/science/article/pii/S1357272514000478)

* [Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy](http://www.sciencedirect.com/science/article/pii/S000991201200269X)

* [Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis](http://err.ersjournals.com/content/22/127/58)

* [The International Journal of Biochemistry & Cell Biology](http://www.sciencedirect.com/science/journal/13572725/52/supp/C)
一本Cystic Fibrosis 2014的整理書

* [Macromolecular complexes of cystic fibrosis transmembrane conductance regulator and its interacting partners](https://drive.google.com/file/d/1C4Qii5mMJIm-BBATRtR5wtyurFuDldIr/view?usp=sharing)
韻安找的Review

* [Phenylalanine-508 mediates a cytoplasmic–membrane domain contact in the CFTR 3D structure crucial to assembly and channel function](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265173/)
一宏google到，用FB分享的。[這個連結圖下有很多篇看起來不錯的論文](http://www.pnas.org/content/105/9/3256/F1.expansion.html)
    ![](https://i.imgur.com/mGK4Mvr.png)
    
* **http://www.jbc.org/content/280/7/5221.short
止善查到的，與本篇論文相較，很像是更深入的探討curcumin的作用，也是2004的論文，可以參照**

* [The Cystic Fibrosis-causing Mutation ΔF508 Affects Multiple Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis](http://www.jbc.org/content/285/46/35825.full)
韻安說還不錯
ABC Transporter, Cystic Fibrosis, Glycoprotein Biosynthesis, Glycoprotein Structure, Protein Folding

* [[The solvent DMSO]](http://onlinelibrary.wiley.com/doi/10.1002/anie.196703181/pdf) 
DMSO作為實驗常用溶劑的論文Fluorometric
measurements of iodide influx

### CFTR與apoptosis & 發炎 & 自噬
* [Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis](https://www.nature.com/articles/s41598-017-06588-z)
癌症常見signal與CFTR關係

* [Elevated miR-155 Promotes Inflammation in Cystic Fibrosis by Driving Hyperexpression of Interleukin-8](http://www.jbc.org/content/286/13/11604.full)

* [MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082784/)
Autophagy
    * [Regulation of mTORC1 and its impact on gene expression at a glance](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678406/)
        * https://en.wikipedia.org/wiki/HIF1A
    * [Common corruption of the mTOR signaling network in human tumors](https://www.nature.com/articles/onc2009352)
    * [mTOR, translation initiation and cancer
](https://www.nature.com/articles/1209888)
    * [The mTOR Signalling Pathway in Human Cancer](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291999/)
    2014 Review, citation 340 times.
    * [Defining the Role of mTOR in Cancer](http://www.sciencedirect.com/science/article/pii/S1535610807001511?via%3Dihub)
    2007 Review, citation 2367 times.


* [Autophagy in lung disease pathogenesis and therapeutics](http://www.sciencedirect.com/science/article/pii/S2213231714001347#s0045)
裡面一節"Autophagy in cystic fibrosis"可看

### CF & Bacterial infection
* [Specific Resistance to *Pseudomonas aeruginosa* Infection in Zebrafish Is Mediated by the Cystic Fibrosis Transmembrane Conductance Regulator](http://iai.asm.org/content/78/11/4542.long)
2010



### Treatment
* [A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR](https://www.nature.com/articles/cdd201622)

* [Nano-based rescue of dysfunctional autophagy in chronic obstructive lung diseases](http://www.tandfonline.com/doi/full/10.1080/17425247.2016.1223040?src=recsys&)
KEYWORDS: Nanoparticle, autophagy, cystic fibrosis, COPD, emphysema, cigarette smoke, Pseudomonas aeruginosa, exacerbation

* [CFTR: folding, misfolding and correcting the ΔF508 conformational defect](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643519/#!po=4.78723)
韻安查到我們看了第一張圖覺得沒有很行第二張圖覺得還不錯，整體看來很不錯的一篇

* **http://www.jbc.org/content/279/39/40629.full
curcumin療法的大反例XDDDD**

    > 是大反例耶！！！[name=Patrick  Wu]
    > 
        簡單看過大反例的，好像沒有東西可以批評。應該是對的，吧><
    > 後續我又查到數篇，再看看有沒有比這個好。本來FUTURE想要做其他SERCA pump的inhibitors，但反例目前有點多，似乎不是好方向ˊˋ[name=止善]

* [Curcumin Stimulates Cystic Fibrosis Transmembrane Conductance Regulator Cl– Channel Activity](http://www.jbc.org/content/280/7/5221.long)
反例




#### NEJM clinical treatment
* [Cystic Fibrosis](http://www.nejm.org/doi/full/10.1056/NEJMra043184)
2005 review
* [Origins of Cystic Fibrosis Lung Disease](http://www.nejm.org/doi/full/10.1056/NEJMra1300109)
2015 review
* [Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR](http://www.nejm.org/doi/full/10.1056/NEJMoa1409547#t=article)
2015
* [CFTR Modulator Therapy for Cystic Fibrosis](http://www.nejm.org/doi/full/10.1056/NEJMe1712335#t=article)
2017.11.03 review
* [Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del](http://www.nejm.org/doi/full/10.1056/NEJMoa1709846#t=article)
2017.11.03
* [Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis](https://resident360.nejm.org/content_items/tezacaftor-ivacaftor-in-patients-with-cystic-fibrosis/)
2017.11.23 NEJM News (內連結為上面那篇)

#### Textbooks
* [Thompson & Thompson Genetics in Medicine, 8th ed, 2014](http://herathospital.org/dl/Thompson%20&%20Thompson%20Genetics%20in%20Medicine,%208e%20(Jun%204,%202015)_(1437706967)_(Elsevier).pdf)
* Thompson & Thompson Genetics in Medicine, 7th ed, 2007
* [Human Melecular Genetics, 4th ed](http://dlx.b-ok.org/genesis/1565000/af79fa7f8653799f65ff1997a0e2d802/_as/[Tom_Strachan,_Andrew_Read]_Human_Molecular_Geneti(b-ok.org).pdf)


## 圖片

![](https://i.imgur.com/foNEFWy.jpg)
[smart - sevier medical art](http://smart.servier.com/)是可以畫很漂亮圖或做ppt的網站！



![](https://i.gbc.tw/gb_img/4/001/498/1498524.jpg)
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