科学家发现特异基因有望成为肥胖相关疾病治疗新靶点

东弗吉尼亚医学院的科学家最近发表了初步研究结论，就是确定了一种特异性基因作为治疗肥胖相关疾病潜在的新靶点。

由国立卫生研究所（NIH）心脏、肺和血液研究院资助的两项研究，主要研究了STAT4基因在2型糖尿病和其他与肥胖相关的心血管疾病发生中的作用。这项研究结果在2010年美国心脏协会年会有关动脉粥样硬化、血栓和血管生物的会议上公布。

“一段时间以来我们已经知道STAT4的是一个'基因开关'，意味着它是一个调节或'打开'免疫细胞的基因。然而，初步研究结果表明，STAT4也参与代谢过程。”生理学副教授，研究的主要作者之一Anca D. Dobrian博士说。

“具体来说，我们发现STAT4可能参与胰岛素抵抗和动脉粥样硬化的发生，微生物学和分子细胞生物学助理教授Elena V. Galkina博士补充说，“假设在老鼠模型的这些结果在人类中也存在，那么STAT4为治疗提供了一个潜在的有吸引力的靶点。”

这些研究的早期结果表明，胰岛素抵抗和动脉粥样硬化，表现为一种动脉壁由于脂肪斑块沉积而增厚为特征的情况，与STAT4水平升高同时出现。

研究人员在老鼠模型中得知，阻断STAT4减少了动脉粥样硬化的发生。同样，敲除STAT4的啮齿类动物模型中给予高脂食物，在它们达到与存在STAT4基因的老鼠相同重量时，并没有出现胰岛素抵抗，而胰岛素抵抗是是2型糖尿病和其他心脏病的危险因素。

“一般来说，”EVMS Strelitz糖尿病中心和内科主任，论文的共同作者Jerry Nadler博士说，“似乎是过多的STAT4的在超负荷工作，产生炎性脂肪而出现这些问题。这一点很有意义，因为在此之前的研究，没有人知道，STAT4参与胰岛素抵抗和动脉粥样硬化。”

这些研究发现为后续研究代谢反应和免疫功能关系奠定了基础。

“现在我们知道STAT4的是一个转录因子，”Dobrian医生说，“下一步将更好地了解其作用机制，最终目标是研发一种药物以阻止或抑制STAT4，并不是整个敲除。”

这位医生说，STAT4是一种特别有吸引力的治疗靶点，因为它只在人体少数类型的细胞存在，因而，把基因表达调整到正常水平的药物，不太可能导致其他副作用。

“在全球，不仅仅是美国，还有大多数发达国家，对于这个最紧迫的公共健康问题，确定一种新的靶向治疗方法是重要的第一步，”Galkina医生说，“如果我们能够研发一种方法来减少与肥胖相关的健康问题，我们可以拯救很多人。”

Galkina 和Dobrian医生也得到美国心脏协会研究经费的资助。

点击此处了解更多

EVMS scientists recently presented preliminary research findings that identify a specific gene as a potential new target for treating obesity-related diseases.

Two research studies funded by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) examined the role of a gene called STAT4 in the development of Type 2 diabetes and other obesity-related cardiovascular diseases. The research was presented at the 2010 annual meeting of the American Heart Association's Council on Atherosclerosis, Thrombosis and Vascular Biology.

"We've known for some time that STAT4 is a 'gene switch,' meaning it is one of the genes that regulates or 'turns on' immune cells. But, our preliminary findings indicate that STAT4 is also involved in the metabolic process," says Anca D. Dobrian, PhD, assistant professor of physiology and lead author of one of the studies.

"Specifically, we've found that STAT4 appears to be involved in insulin resistance as well as the development of atherosclerosis," adds Elena V. Galkina, PhD, assistant professor of microbiology and molecular cell biology. "Assuming these results in rodent-models hold true for humans, STAT4 offers a potentially attractive target for therapy."

Early findings in these studies indicate that insulin resistance and atherosclerosis, a condition characterized by the thickening of artery walls due to fatty plaque deposits, occur in conjunction with elevated levels of STAT4.

The researchers learned that eliminating STAT4 in rodent models reduced the development of atherosclerosis. Similarly, eliminating STAT4 in rodent models given a high-fat diet revealed that while the rodents gained the same amount of weight as rodents with the gene, they did not develop insulin resistance -- which is a risk factor for Type 2 diabetes and other heart problems.

"Basically," says Jerry Nadler, MD, director of the EVMS Strelitz Diabetes Center, chair of internal medicine and co-author on both papers, "it appears that excess STAT4 is working in hyper-drive, leading to inflamed fat which can produce these problems. This is significant because prior to this study, no one knew that STAT4 was involved in insulin resistance or atherosclerosis."

These findings lay the groundwork for pivotal follow-up studies on the relationship between metabolic responses and immunity.

"Now that we know STAT4 is a factor," Dr. Dobrian says, "the next steps will be to work on better understanding the mechanisms behind it with the ultimate goal of developing a drug that blocks or inhibits STAT4, without eliminating it entirely. "

The doctors say that STAT 4 is a particularly attractive target for treatment because it exists in only a few cell types throughout the body, and, therefore, any drug that regulates the gene's expression to maintain normal levels is less likely to cause other side effects.

"This is an important first step in identifying a new target for treatment of the most urgent health problem throughout not only the United States, but much of the developed world," Dr. Galkina says. "If we can develop a way to reduce the health problems associated with obesity, we can save a lot of people."

Drs. Galkina and Dobrian also are funded by research grants from the American Heart Association.

点击此处参与丁香园论坛讨论