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一年两针PCSK9 RNAi显著降低LDL

新闻一年两针PCSK9 RNAi显著降低LDL

【新闻事件】:昨天Medicine’s Company公布了其PCSK9 RNAi药物inclisiran在一个叫做ORION-3的二期临床中期分析结果。ORION-3是双盲二期临床ORION-1之后的开放标签长期跟踪实验,ORION-1的用药组和安慰剂对照组分别加入ORION-3的第一、第二组。昨天公布的是第一组结果(即ORION-1的用药组患者继续使用inclisiran),结果用药210天后LDL-C比ORION-1入组前基线下降51% (64.0 mg/dL),疗效与总给药次数无关。安全方面没有发现重要安全信号。如果从ORION-1入组开始算这些患者已经观测了三年,每年两次注射inclisiran可以安全降脂50%以上是个重要进步。这个试验患者入组前使用最大耐受剂量已有疗法仍无法有效控制LDL-C。Inclisiran在三个不同人群的三期注册临床正在进行,第一个今年就会揭晓。 【药源解析】:PCSK9是少见的项目开始前就算高确证靶点之一,不仅与LDL-C关系非常明确而且LDL-C水平与心血管疾病关联也是医学上最可靠的关联之一,所以当年的PCSK9竞争异常激烈。安进的Repatha一路领先、但赛诺菲用6750万美元买个史上首张PRV反超,Praluent第一个上市用于罕见家族性高血脂症。Repatha第一个在更大的有CV风险高血脂人群显示心血管收益,安进一度差点以侵犯专利为由将赛诺菲的Praluent赶出市场。赛诺菲反击成功、保留参赛资格,随后也在CV风险高血脂人群显示心血管收益。处于第三的辉瑞则因药物产生中和抗体在几个三期试验后终止了该项目。 但是人算不如天算的是当这两个高质量药物成功完成所有大型临床试验后,支付的江湖与他汀时代已经完全不同。孤儿药的大规模上市给支付体系带来前所未有的压力。这些孤儿药虽然单个看患者有限、即使高价也不会对支付系统带来太大压力,但是作为一个群体很快成为药品支出的一个重要组分。PSCK9抗体虽然效果很好但因为可以使用的人群太太所以如果按厂家定价交钱支付部门将面临破产,各国支付部门以收益有限为由要求厂家降价。现在两个药物都以半价销售、业绩也与原来预测的超重磅地位相去甚远。单价乘以患者人数计算销售的时代已经过去,如果总量太大除非患者受益十分显著否则支付部门爱莫能助。 PCSK9蛋白表达水平较高,所以需要较高剂量的抗体、增加了成本。另外抗体需要每月注射1-2次,对于慢性病也是个不大不小的障碍。RNAi理论上可以只需催化量,因为一个分子RNAi即可激活降解PCSK9 mRNA的RISC酶系统。这导致RNAi一是不需要与高浓度的PCSK9较劲,二是可以降低给药频率。Inclisiran只需半年甚至一年给药一次,有些患者据说已经忘了自己在接受治疗。现在更诡异的黑科技基因编辑可能一针给药、终生受益,刚刚成立的Verve就准备开发PCSK9的CRISPR编辑技术。 MDCO另一个关键产品、HDL药物Apo-A1 Milano/磷酸酯组合MDCO-216在2016年惨败, MDCO为了开发Inclisiran倾其所有,自2016年始先后将止血/凝血产品、包括历尽千辛万苦上市的Cangrelor(波立维类似物)和抗生素业务分别变卖。这一系列事件令MDCO从多产品药厂成为单产品的开发阶段生物技术公司,单即使这样现在能否攒够学费让Inclisiran完成学业也不是板上钉钉的事。Inclisiran最早由RNAi先驱企业Alnylam开发,后与MDCO合作。Inclisiran利用的是肝靶向的GalNac技术,如果上市将成为首个靶向大众病的RNAi。这也将令Verge的基因编辑前景更加明确,这些就在几年前连治疗罕见病都存疑的高科技有望飞入寻常百姓家。详情>>

2019-05-21 00:00:00

论文LIMS1基因位点的基因组错配与同种异体肾移植排斥反应

BACKGROUND In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor–recipient pairs. We defined genomic collision as a specific donor–recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P=9.8×10−5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor–recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P=6.5×10−5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P=4.7×10−8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.)展开>><<收起

N Engl J Med 2019; 380:1918-1928  0
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挖掘25年的数据揭示了亨廷顿病发病年龄的新预测因子

新闻挖掘25年的数据揭示了亨廷顿病发病年龄的新预测因子

Investigators at the University of British Columbia (UBC)/Centre for Molecular Medicine & Therapeutics (CMMT) and BC Children's Hospital have examined more than 25 years of data to reveal new insights into predicting the age of onset for Huntington disease. "This discovery may enable us to provide families with additional information," said lead author Galen Wright, a research associate in the UBC faculty of medicine, CMMT and BC Children's. "It could also potentially improve disease management by providing genetic counsellors with valuable data in the future." Huntington disease is an inherited disorder that affects one in approximately 7,000 Canadians. For every affected person, there are four to five individuals that carry the gene mutationthat causes the disease, but are not yet ill. The disease often begins around age 40. Symptoms include motor, cognitive and psychiatric changes. Huntington disease is caused by a single mutation in the huntingtin gene, where patients carry an expanded stretch of repetitive DNA. While the length of this mutation has long been regarded as the greatest indicator of when (and whether) an individual will exhibit symptoms of the disease, researchers at UBC have uncovered a genetic variant that also significantly influences age of onset in patients. "Our study reveals that age of onset in Huntington disease is influenced not only by the length of the expansion mutation, but also by the DNA sequence directly adjacent to this repetitive sequence," said senior author Dr. Michael Hayden, a Killam professor of medical genetics and director emeritus for the CMMT, which is part of the faculty of medicine at UBC and located at BC Children's. This is the key finding in a new study published today in the American Journal of Human Genetics. While previous studies of the huntingtin gene have focused on the length of the string of glutamine building blocks in the DNA of the gene, this study examined variants in the DNA sequence encoding for these glutamine building blocks and the relationship between these variants and the age of onset of the disease. The DNA sequence that causes Huntington disease is primarily made up of repeats of three letters of DNA, CAG, which encode the protein building block, glutamine. But UBC researchers have shown that the presence of another glutamine building block, CAA, significantly impacts the disease. In individuals where the CAA sequence is replaced with a CAG sequence, patients were found to present with the disorder decades earlier than expected, despite carrying an identical number of glutamine amino acids. "Now we know that the age of onset in Huntington disease is significantly impacted by the length of uninterrupted CAG sequence," said Hayden. The length of uninterrupted CAG sequence also appears to contribute to somatic instability. The researchers screened samples from patients in the UBC Huntington disease biobank for the variant in the huntingtin gene, to examine age of onset and whether the mutation was more likely to expand to longer repeat lengths in the blood. Hayden established this bank—which now contains approximately 8,000 specimens—in 1986 in an effort to conduct such studies. Hayden's team hopes to screen additional DNA samples to further refine age of onset prediction models for people from families with Huntington disease with this variant, and to look at how these variants express themselves in brain tissue.详情>>

2019-05-17 00:00:00
基因组碰撞可解释许多肾移植失败的原因

新闻基因组碰撞可解释许多肾移植失败的原因

A genomic collision could explain why many kidney transplants fail, even when donors and recipients are thought to be well-matched, according to a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons. This genomic collision is a genetic incompatibility between kidney donor and recipient, causing the recipient to mount an immune attack against the donor protein. The findings, published online today in the New England Journal of Medicine, could lead to more precise matching between donors and patients, and reduce kidney transplant failures. The same genomic collision may also potentially occur in heart, liver, and lung transplants. A Different Possible Mechanism for Kidney Rejection A successful organ transplant depends in large part on assuring genetic compatibility between donor and recipient. This is done by matching the donor and recipient's human leukocyte antigens (HLAs)—cell surface proteins that help the immune system determine which cells are foreign—as closely as possible. But HLA mismatches can only explain only about two-thirds of transplants that fail for immunological reasons. "The rest of those failures are probably due to less common antigens, or so-called minor histocompatibility antigens. However, the identity of most of these antigens and how they lead to rejection is largely not known," says co-senior author Krzysztof Kiryluk, MD, the Herbert Irving Assistant Professor of Medicine at Columbia University Vagelos College of Physicians of Surgeons. The researchers hypothesized that a person whose genome carries a kidney gene with a deleted section might be especially sensitive to organs from a donor whose genome carries the full-sized gene. "The recipient would then be exposed to a protein their immune system would sense as foreign," says Kiryluk. To test their hypothesis, they screened 705 kidney recipients transplanted at Columbia University Irving Medical Center for deletions in 50 kidney genes that were present as full-sized versions in the donor. The deletions associated with rejection were then confirmed in an additional 2,004 donor-recipient pairs from three international transplant cohorts. What the Study Found The study found that kidney recipients with two copies of a deletion near a gene called LIMS1 had a significantly higher risk of rejection when the donor kidney had at least one full-sized version of the same gene. The risk of rejection was 63 percent higher among the donor-recipient pairs with this genomic collision, compared to those without this mismatch. "To put this into perspective, the risk of rejection from LIMS1 mismatch is roughly three times as high as the risk due to a single allele mismatch in the HLA," Dr. Kiryluk says. Kidney transplant recipients with two copies of the deletion who developed rejection had detectable levels of anti-LIMS1 antibodies in their blood—further evidence that this genomic collision contributes to rejection. "The exact mechanism by which this deletion exerts its effects is unknown," says Kiryluk. "It's likely that it reduces the amount of LIMS1 protein produced, since we find that individuals with two copies of the deletion have lower levels of LIMS1 gene transcript in their kidneys. When these individuals are exposed to a high level of LIMS1 protein in a newly transplanted organ, their immune system is more likely to recognize the LIMS1 antigen as foreign, resulting in rejection." Transplanted organs commonly experience a significant period of low oxygenation, which appears to compound the genomic collision. In cells that produce LIMS1, the researchers found that low oxygen levels increase LIMS1 production on the cell surface, which may increase the risk of an immune attack. 1 in 7 Transplants in Some Populations May Be Affected LIMS1 mismatches would be expected to occur in approximately 12 to 15 percent of transplants from unrelated donors among persons of European and African ancestry, but it would be very rare among persons of East Asian ancestry because the deletion is very rare in these populations. "LIMS1 mismatches could be avoided by pre-transplant genetic screening," Kiryluk says. "But first we need to validate our findings in larger studies." The findings may apply to other types of organ transplants since LIMS1 is also expressed in the lung, heart, and liver. Similarly, other genetic incompatibilities may also be contributing to rejection of these organs. "This project illustrates how genetic analysis is empowering clinical care by enabling better matching and the antibody test potentially presents a noninvasive method for screening for organ rejection in individuals with an existing transplant," says co-senior author Ali G. Gharavi, MD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. The LIMS1 gene has gone previously undetected in earlier searches, partly due to the limited sample size of previous studies, Kiryluk says. "We estimate that a traditional genome-wide association study would need to analyze a minimum of 13,000 kidney recipients to find this gene," he adds. "The genomic collision approach provides a new method to find additional mismatches in a smaller number of donor-recipient pairs. And coupled with new methods of antibody detection, is likely to propel future discoveries in this area." The study is titled, "Genomic Mismatch at LIMS1 Locus and Kidney-Allograft Rejection."详情>>

2019-05-16 00:00:00
更多关于遗传性胆固醇紊乱背后遗传学的线索

新闻更多关于遗传性胆固醇紊乱背后遗传学的线索

High cholesterol is a risk factor for heart disease, but not all forms of it are the same. An underdiagnosed genetic condition called familial hypercholesterolemia can cause dangerously high levels of cholesterol at an early age. While scientists have determined FH is caused by genetic mutations that affect the body's ability to remove LDL, or "bad" cholesterol, they haven't pinned down all the genes involved for nearly 1 in 3 people who have FH. But that may be beginning to change. Scientists presented preliminary research at the American Heart Association's Vascular Discovery conference in Boston this week showing more clues to the genetic roots of FH. National Heart, Lung, and Blood Institute researchers screened 19,114 genes and identified transgelin (TAGLN) as one of the genes of interest. Previous studies have found this gene could be associated in LDL metabolism. When researchers disabled the TAGLN gene in cells, some cells tried to compensate. "The cell tries to make more cholesterol because cholesterol is vital for the cell to survive," said Diego Lucero, the study's lead author and a postdoctoral fellow at the NHLBI. "Understanding this is important because it might have impacts on the magnitude of the clinical presentation of the disease." People with FH are exposed to chronically high levels of LDL from an early age, and their risk for premature heart disease is 20 times greater than the general population, according to the FH Foundation. Over time, the condition can lead to atherosclerosis b the buildup of plaque and narrowing of artery walls. As a result, signs of heart disease can show up decades earlier in people with FH compared to the general population. The condition affects approximately 1 in 250 U.S. adults. Yet, it remains largely underdiagnosed and undertreated. "Less than 10 percent of those who have (FH) have actually been diagnosed, which leads to a lot of premature morbidity and mortality," said Dr. Samuel Gidding, chief medical officer for the FH Foundation. Someone who carries the altered gene has a 50% chance of passing it on to their children. Yet, the challenge is diagnosing FH. Health care providers may not understand the difference between general high cholesteroland FH and may not screen high-risk people, said Gidding, who was not involved in the new study. FH can be diagnosed with a simple blood test and a reported family history of cardiovascular disease. Doctors look for LDL levels over 190 in adults and over 160 in children, and onset of heart disease before age 60 in men and before 50 in women. Genetic testing can confirm the diagnosis. Once identified, there are effective ways to treat the condition, Gidding said. Early treatment with medications, as well as maintaining a heart-healthy lifestyle, can lower the risk of premature heart attacks and strokes. The new research and further work identifying new genes involved in the development of FH could lead to better diagnosis and treatment, Gidding said. "Anytime an individual gene like this could help explain variations in lipid level, it could be a drug target."详情>>

2019-05-16 00:00:00
唤醒干细胞,释放大脑再生潜能

新闻唤醒干细胞,释放大脑再生潜能

The human body has powerful healing abilities. But treating brain disorders is no easy task, as brain cells—neurons—have limited ability to regenerate. Nonetheless, stem cells are a form of natural backup, a vestige of our days as still-developing embryos. The difficulty is that with age, neural stem cells 'fall asleep' and become harder to wake up when repairs are needed. Despite efforts to harness these cells to treat neurological damage, scientists have until recently been unsuccessful in decoding the underlying 'sleep' mechanism. Now, researchers at Kyoto University studying brain chemistry in mice have revealed the ebb and flow of gene expression that may wake neural stem cells from their slumber. These findings, which may also apply to stem cells elsewhere in the body, were recently published in the journal Genes & Development. "No one before us has directly compared active stem cells in embryos with inactive, 'quiescent' adult stem cells," says group leader Ryoichiro Kageyama of Kyoto University's Institute for Frontier Life and Medical Sciences, who points out that at least two genes and their associated proteins regulating activation had already been identified. The team focused their attention on protein 'Hes1', which is strongly expressed in the adult cells. This normally suppresses the production of other proteins such as 'Ascl1', small amounts of which are periodically produced by active stem cells. Monitoring the production of the two proteins over time, the team pinpointed a wave-like pattern that leads to stem cells waking up and turning into neurons in the brain. When they knocked out the genetic code needed to make Hes1, the cells started to make more Ascl1, which then activated almost all the neural stem cells. "It is key that the same genes are responsible for both the active and quiescent states of these stem cells," Kageyama says. "Only the expression dynamics differ between the two. A better understanding of the regulatory mechanisms of these different expression dynamics could allow us to switch the dormant cells on as part of a treatment for a range of neurological disorders."详情>>

2019-05-15 00:00:00
研究发现了负责多发性硬化症慢性炎症的机制

新闻研究发现了负责多发性硬化症慢性炎症的机制

Multiple sclerosis (MS) is an autoimmune disease in which the immune system turns on its own cells and attacks them for reasons that are not yet known. Scientists from the Institut Pasteur have shown that ancient viruses are involved in the acute inflammatory defense response that may contribute to the disease. Multiple sclerosis (MS) is an incurable inflammatory autoimmune disease that leads to irreversible damage to the brain and spinal cord. It is also associated with the reactivation of ancient viruses that were inserted into human DNA during the evolution of humankind. It was therefore long thought that multiple sclerosis was due to a viral infection. "Our study shows that reactivation of ancient viruses does not correspond to an infectious phenomenon, but to a defense response of the body when faced with an acute inflammatory phenomenon," explains Christian Muchardt, head of the Epigenetic Regulation Unit at the Institut Pasteur. Viral sequences were neutralized during evolution and no longer represent a source of infection. But these sequences are a source of external DNA containing information about virus behavior. Cells have therefore been able to control these sequences to detect infections as quickly as possible and turn on their defense genes during an attack. These viral sequences are used to control defense genes in stem cells. They lie dormant in adult cells, and it is the more traditional sequences that become active. By examining samples from patients with MS, the scientists observed that regulatory sequences of viral origin emerged from their dormant state and were responsible for abnormal expression of several pro-inflammatory genes. To conclude, in multiple sclerosis, activation of viral sequencesdoes not correspond to an infectious phenomenon but to the unexpected use of regulatory sequences, leading to chronic excessive inflammation. "The discovery of this mechanism, linked to epigenetic phenomena, may one day pave the way for management of MS using small molecules that inhibit chromatin modification enzymes," says Christian Muchardt.详情>>

2019-05-14 00:00:00
突变如何导致神经退行性疾病

新闻突变如何导致神经退行性疾病

Scientists have discovered how mutations in DNA can cause neurodegenerative disease. The discovery is an important step towards better treatment to slow the progression or delay onset in a range of incurable diseases such as Huntington's and motor neurone disease – possibly through the use, in new ways, of existing anti-inflammatory drugs. The team of scientists has shown experimentally, for the first time, how mutations ultimately set off an anti-viral like inflammatory response in cells that leads to cell death and, over time, progressive neurological damage. Led by the University of Adelaide, the study published in Human Molecular Genetics is the culmination of over a decade of research with researchers at the Victor Chang Research Institute in Sydney, seeking to understand how DNA mutations result in neurological damage. This study investigates the outcomes of a mutation linked to Huntington's disease and 20 other neurodegenerative diseases, including some forms of motor neurone disease. But it also may have implications for the progression of neurodegenerative diseases which aren't necessarily inherited, such as Alzheimer's and Parkinson's, which evidence suggests are caused by a similar inflammatory response to environmental triggers. "Together these conditions affect millions of families worldwide, and there are no cures or effective treatments," says project leader Rob Richards, Professor of Genetics in the University of Adelaide's School of Biological Sciences. "If the new mechanism we have discovered proves to be correct, it will transform the field, providing a different way of thinking about these diseases and offering new opportunities for medical intervention." The so-called 'DNA repeat diseases' – named because of the repeat sequences found in the DNA of patients – share many common features in their symptoms, but the mechanisms by which symptoms arise have previously been thought to be different for each. "We've known what mutations are involved for some years, and the set of outcomes that result, but, until now, we've not known how one leads to the other. This new research shows us how each of these diseases can be caused by the same underlying cellular pathway." The study results centre around RNA, the molecule in our cells which is the intermediate step between the DNA in chromosomes and the proteins that are the cells' main functional components. The DNA provides a blueprint for producing RNA that is then normally 'bar-coded' to ensure cells recognise it as "self", distinguishing it from the RNA of a foreign invader, such as viruses. Using the experimental model fly Drosophila, Professor Richards and his team showed that the affected, 'double-stranded RNA' was instead recognised as foreign to the body, or "non-self". "This elicits an anti-viral like, auto-inflammatory response that leads to neuronal destruction and death, in time causing progressive neurological damage," says Professor Richards. "The abnormal RNA is made from regions of repeated DNA sequences that are found in greater numbers in people affected with Huntington's and some other neurodegenerative diseases." Professor Richards says there are existing drugs for other types of auto-inflammatory disease, which may prove to be effective in treating the symptoms of these diseases, by inhibiting the anti-viral inflammatory response.详情>>

2019-05-14 00:00:00
深入研究关节炎药物对基因表达的影响

新闻深入研究关节炎药物对基因表达的影响

A new computational framework has revealed key differences between four rheumatoid arthritis medications and their impact on biological pathways in mice. Niki Karagianni of Biomedcode Hellas SA, Greece, and colleagues present their new approach and findings in PLOS Computational Biology. People with rheumatoid arthritis often receive medications that target and inhibit Tumor-Necrosis Factor (TNF), a protein involved in the painful and damaging inflammation characteristic of the disease. While several anti-TNF drugs are used widely with comparable clinical success, the details of their different molecular effects on biological processes have been unclear. To fill this gap, Karagianni and colleagues employed a mouse model of chronic inflammatory polyarthritis—mice that express the human TNF and develop symptoms and signatures that closely mirror the human form of the disease. The diseased mice received treatment with one of four anti-TNF drugs (Remicade, Cimzia, Humira, or Enbrel), or for comparison, none of the drugs. The researchers then compared them to healthy mice. After treatment, the researchers collected joint tissue from all the mice and analyzed their transcriptomes—the complete set of messenger RNA molecules in the tissues, which indicates which genes are turned on or off. Then, they applied a series of computational steps to the transcriptome data in order to compare the effects of the four different drugs. The analysis revealed previously unknown differences in the way the four drugs affect gene expression in diseased mice. Some of these differences were found for genes directly involved in arthritis, but many were found in non-arthritis-related genes, such as genes involved in cardiovascular disease and other conditions that may occur alongside arthritis. "Perhaps the most important result to come out of our study is the large number of down-regulated genes in the diseased animals, which are associated with functions and pathways that were until recently largely overlooked," says study co-author Christoforos Nikolaou. "These could provide additional insight into arthritis pathology mechanisms." The new computational framework developed for this study could be repurposed for detailed comparisons of other drugs in other diseases. To help facilitate this, the researchers are working to organize the system into an automated, standalone package.详情>>

2019-05-13 00:00:00
即使没有遗传倾向,压力过大的人也会患上心律失常

新闻即使没有遗传倾向,压力过大的人也会患上心律失常

When encountering a charging predator or participating in a triathlon, the human heart responds by beating faster to increase blood supply to muscles. It is a natural and well-understood reaction to stress. However, there are times when emotional or physical stresscauses the heart to beat with an irregular or abnormal rhythm, a condition called arrhythmia that is the focus of research by Dr. Filip Van Petegem of the Department of Biochemistry and Molecular Biology at the University of British Columbia. In a paper published May 8, 2019 in Molecular Cell, Van Petegem sheds new light on how two proteins interact in the heart in cases of stress-induced arrhythmia, and on potential treatment. "The big picture of our work is to understand how stress signals affect a protein in the heart muscle that is critical for heart contraction," said Van Petegem. In a stress situation, that heart protein receives a tag from another protein, and the tag allows more efficient delivery of calcium, key to contraction. "Normally, the protein is tagged, the heart rate goes up, then the tag is removed and all is fine," he said. "This process allows the heart to adapt to the needs of the environment. "But if the tags stay too long or there are too many tags, calcium can be delivered between heartbeats. That starts to affect the electrical signals in the hearts and can cause arrhythmia." The full Ryanodine Receptor (grey) with the enzyme (blue) and the domain that receives the tag (red). Credit: Canadian Light Source Arrhythmia in people with no genetic predisposition is an acquired condition, he explained, "and once you have it, it often progresses." It serves as a warning signal for more persistent forms of arrhythmia. "Our research looked at the protein that delivers the tag—how it recognizes the protein on which it has to deliver the tag, and how that tag delivery happens." To find the answer, Van Petegem and his colleagues created crystals from the proteins. They then used X-ray diffraction at the Canadian Light Source (CLS) at the University of Saskatchewan to produce 3-D images that revealed a structure that shows how the tag is delivered. "The structure was quite a surprise," he said. "We thought, this is weird, but we tested it in various ways and it was always there." With this new understanding of the tag-delivery mechanism between proteins, "we've identified a lot of areas where we think a small molecule could be used to interrupt the excessive tagging. It's hypothetical but it's definitely an avenue worth pursuing." In addition to identifying the structure between proteins, Van Petegem's research also found that the structure was subject to genetic mutation, and identified how the tag changes the properties of the protein. Van Petegem pointed out the published research involved only one of two main proteins that deliver tags. The second "is equally as important if not more important, and they seem to interfere with each other." He hopes to repeat the study on the second protein if crystals can be produced, "but that can sometimes be very tricky."详情>>

2019-05-13 00:00:00