找到慢性疼痛可能的基因機轉

作者：Megan Brooks  
出處：WebMD醫學新聞

　　May 7, 2010 — 根據一項神經痛鼠類模式的新研究，慢性疼痛可能肇因於週邊神經系統許多未被注意的基因重組。
　　
　　明尼蘇達羅徹斯特梅約診所腫瘤科與麻醉科Andreas Beutler醫師在一封給Medscape神經學的電子郵件中表示，其研究結果顯示，轉錄組重組可能是神經疾病如慢性疼痛的一個重要機轉。他與其同事們的結論是，這些發現最終會讓我們找到「轉錄治療」的標的。
　　
　　Beulter醫師與其同事們描述他們的研究使用一種稱為「範型轉移」的序列技術進行研究，結果線上發表於5月7日的基因體研究（Genome Research）期刊。
　　
　　Beulter醫師在一項來自梅約診所的書面聲明中表示，超高流量mRNA序列分析（mRNA-seq）提供了一種更高敏感度、動態範圍以及更有效率的非誤差基因圖譜，相較於過去以微陣列為基礎的方法，可能是個更有效率的新方法，可提供神經科學研究更廣泛的陣列。
　　
　　Beulter醫師向Medscape神經學表示，很重要的，我們是第一個採用這些技術於神經疾病模式的研究。
　　
　　他與他的同事們進行於相鄰L5脊椎神經脊椎神經結紮造成的慢性神經疼痛鼠類L4背根神經節進行mRNA-seq。
　　
　　該團隊在其研究報告中表示，研究者之所以挑選慢性疼痛，是因為這是個在功能基因體層級仍然不完全瞭解的一種常見神經異常。
　　
　　研究者們報告，脊椎神經結紮後2週，在失能但結剖構造完整的L4背根神經節發現，12.4%已知基因被誘發，而7%被壓抑。這些變化在脊椎神經結紮2個月後仍然明顯。
　　
　　使用讀取叢集分類器，以強烈測試特質（接受操作特徵面積為97%），作者在背跟神經節觀察到10,464個全新的外顯子，潛在地牽涉到慢性疼痛，包括一46個外顯子作為痛覺傳導物質P的共同受體。
　　
　　根據科學家們表示，21.9%新發現的外顯子被發現在這個神經痛動物模式中是失調的。
　　
　　相較於過去於同樣鼠類疼痛背根神經節模式下，根據微陣列技術得到的資訊，以mRNA-seq技術，他們可以找出更多的基因表現變化。
　　
　　重要的是，mRNA-seq展現出神經系統中轉錄組重組技術可能比使用微陣列技術的研究更加廣泛，這引發了某些神經疾患，例如疼痛，可能在未來被改寫為服從於轉錄療法的基因表現改變疾病。
　　
　　這項研究部分由國家神經疾病與中風機構贊助。部分mRNA-seq技術由加州Hayward Illumina有限公司研發。Beutler醫師表示沒有相關資金上的往來。試驗作者Gary P. Schroth博士，lllumina公司的技術研發部門主任是這項研究的合作者。


Possible Genetic Mechanism for Chronic Pain Identified

By Megan Brooks
Medscape Medical News

May 7, 2010 — Chronic pain may be caused by the inadvertent reprogramming of numerous genes in the peripheral nervous system, according to new research in a rodent model of neuropathic pain.

"Our results suggest that transcriptome reprogramming may be an important mechanism of neurological diseases such as chronic pain," Andreas Beutler, MD, from the Department of Oncology and Anesthesiology, Mayo Clinic, Rochester, Minnesota, noted in an email to Medscape Neurology. The finding could eventually lead to the identification of targets for "transcription therapy," he and colleagues conclude.

Dr. Beutler and colleagues describe their research using what they call a "paradigm-shifting" sequencing technique online May 7 in Genome Research.

Ultra–high throughput mRNA sequencing (mRNA-seq) "offers greater sensitivity, dynamic range and more efficient unbiased genetic mapping compared to the previous microarray-based methods and may be an efficient new approach to a wide array of problems in neuroscience research," Dr. Beutler explained in written statement from the Mayo Clinic.

"Importantly, our study is the first to apply the technology to a neurological disease model," Dr. Beutler told Medscape Neurology.

He and colleagues performed mRNA-seq on the L4 dorsal root ganglion of rats with chronic neuropathic pain induced by spinal nerve ligation of the neighboring L5 spinal nerve.

The researchers chose chronic pain because it is a common neurological disorder that is "incompletely understood at the functional genomic level," the team explains in their report.

Two weeks after spinal nerve ligation, 12.4% of known genes were induced and 7% were suppressed in the dysfunctional but anatomically intact L4 dorsal root ganglion, the researchers report. These alterations were still apparent 2 months after spinal nerve ligation.

Using a read cluster classifier with strong test characteristics (receiver operating characteristic area, 97%), the authors discovered 10,464 novel exons in the dorsal root ganglion potentially involved in chronic pain, including a 64-exon coreceptor for the nociceptive transmitter substance P.

According to the scientists, 21.9% of the newly discovered exons were found to be dysregulated in this animal model of neuropathic pain.

With mRNA-seq, they say they identified significantly more gene expression changes than expected based on previous microarray studies performed on dorsal root ganglion in similar rat pain models.

"Importantly, mRNA-seq demonstrates that transcriptome reprogramming in the nervous system may be more extensive than recognized by microarray studies raising the possibility that some neurological disorders such as pain may be recast in the future as diseases of altered gene expression amenable to transcription therapy."

This research was supported in part by the National Institute of Neurological Disorders and Stroke. A portion of the mRNA-seq technology was developed by Illumina, Inc, of Hayward, California. Dr. Beutler has disclosed no relevant financial relationships. Study coauthor Dr. Gary P. Schroth, head of the Illumina technology development lab, was a collaborator on the study.

Genome Res. Published online May 7, 2010.