Nobel Laureate Greg: HIF-1-Related Drugs Are Effective for Some Patients

October 29 , today , the second World Forum of Top Scientists opened in Shanghai , with the theme of “Science and Technology, for the Common Destiny of Mankind” , which lasted for four days : October 29 to November 1 . At the forum, Greg Semensa, the 2019 Nobel Prize winner in Physiology or Medicine, gave a speech entitled “Oxygen Steady State: A Balanced Behavior”.

诺奖得主格雷戈:HIF-1相关药物对部分患者有效

Mr Gregg says there are hundreds of millions of cells in the body that need oxygen to function properly. We found that the more hypoxia, the more HIF-1 is produced, and in 2005 scientists discovered that HIF-1 can be hydroxyl-regulated by oxygen, and to see a mechanism that directly links oxygen content to HIF-1.

诺奖得主格雷戈:HIF-1相关药物对部分患者有效

In cardiovascular disease, heart tissue is affected once oxygen is lacking. About 4,000 target genes are regulated by HIF-1, and HIF-1 also plays a role in metabolism.

As scientists continue to study, the development of the human circulatory system is also regulated by HIF-1, from the liver, duodenum to the spinal cord, there is a presence of HIF-1.

One disease, called congenital polyleocytes, causes an abnormal increase in red blood cells in the patient’s body, which can lead to diseases such as stroke. They had a lead change in VHL and HIF-1 and HIF-2 alpha in the gene pathway, which are some of the factors that innately control red blood cell production.

Greg believes that HIF-1 is involved in so many regulatory pathways that we can contain drugs such as HIF-1 inhibitors to treat related diseases. The results of the study found that some drugs can have a good effect on some tumors. (River rain)

The 2nd World Forum of Top Scientists was sponsored by the World Association of Top Scientists, hosted by the Shanghai Municipal People’s Government and guided by the China Association of Science and Technology. A total of 8 thematic summits were set up, with 65 Nobel Prizes, Wolf Prizes, Lasker Prizes, Turing Prizes, Fields Prizes, MacArthur Genius Awards and other world’s top scientific award winners, more than 100 Chinese academicians, and the world’s outstanding young scientists to attend the in-depth dialogue. Around the topic of space, space, space, photons, climate, energy, life, genes, etc. that will change the fate of mankind, we will create a summit on artificial intelligence calculation algorithms, brain science and neurodegenerative diseases, innovative drug research and development and translational medicine, life sciences, hydrocarbon bonds and new chemistry, new energy and new materials, black holes and space science, economy and finance.

The following is the full text of the speech shorthand:

I want to say that the human body has 10 14 square cells, each of which requires a continuous supply of oxygen. We’ve had to understand for the last 30 years how the oxygen balance is achieved. How is supply and demand balanced?

We can see that oxygen acts on mitochondria in cells, turning food into energy, and requires the circulatory and respiratory system to continue to function. We also have transcription factors that play a role at different levels. We begin to understand how our blood cells work, including how red blood cells transmit oxygen to various parts of the body. There is also EPO (a erythronis-promoting factor) that allows our bone marrow to produce red blood cells, and when oxygen levels drop in the body, EPO’s production in the kidneys increases.

How do we control the generation of EPO? We found that there are 33 excerpts of NDA in the EPO gene that can be changed. We assume that the order of DNA excerpts changes, and we use DNA to evolve DNA, called HIF-1 (hypoxia-inducing factor 1), which enables the production of ePO genes in the kidneys. At the same time, we also found that HIF-1 is generated in large quantities as oxygen levels in the body are reduced to 6%. At 3-6%, a decrease in oxygen content can lead to a large number of HIF-1 generation, so the more hypoxia, the more HIF-1 is generated.

The mechanism of regulating this mechanism can be seen in this PPT, and in 2005 William Keeling and Peter Ratcliffe can see the description on the PPT for the regulation of hIF-oxygen-dependent hydroxylation. The oxygen molecules in HIF-1 can be affected by VHL and can degrade HIF-1, which is in the case of normal oxygen. In the case of hypoxia, the action of enzymes is inhibited and HIF-1 accumulates in cells, so such a mechanism allows us to directly link oxygen content to HIF activity. Lack of oxygen may cause cells to consume more oxygen, for example, in cancer cells, in cardiovascular disease, heart tissue is also affected, HIF-1 has a large number of targeted cell production, there are about 4,000 target genes are regulated by HIF-1. Some of these genes can increase oxygen transfer and reduce the production of red blood cells. In addition, it can also achieve the generation of blood vessels. HIF-1 can be metabolized by glycolysis.

Our study of HIF-1 alpha has found that circulatory development requires HIF-1, and that if the heart is not fully developed, its blood vessels and blood can have problems. All three very important body mechanisms are dependent on HIF-1. In addition, there are a number of related cellular genes, including HIF-1 alpha, HIF-2 alpha, HIF-3 alpha. HIF-2 and HIF-3 alpha are found only in the cell types of certain vertebrate species, while HIF-1 alpha is found in almost all nuclear cell types in almost all post-animal species. These are the differences between vertebrates and invertebrates, which not only open a gene when there is blood loss, not only the kidneys produce EPO, but also a series of genes that absorb iron from the duodenum, because we need iron to have transferrins to bring more red blood cells to our body.

After we reduced triamcintoin to divalty iron, the iron was transferred into the blood and combined with red blood cells by transferrin. The genes shown here are regulated by HIF-2, from the liver to the duodenum to the blood and spinal cord.

This system is essential to ensure the production of red blood cells in the human body, and we have a very rare disease on our side called congenital red blood cell hyperplasia, which means that too many red blood cells are produced in the body, which can lead to stroke and heart disease, and when we examine these patients, They have one such situation in the genetic pathway. They have a pioneering condition in VHL and HIF-1 and HIF-2 alpha, which are some of the factors that innately control red blood cell production. In addition, we found an important phenomenon, protalythane hydroxylase inhibitors can stimulate red blood cell production in patients with chronic kidney disease.

We also know from patients that if these two activities are reduced, the number of red blood cells increases, and then increases the survival, proliferation and differentiation of red progenitor cells, which is very important for patients with chronic kidney disease, because if you have kidney disease, especially chronic kidney disease, it causes the body to stop producing EPO. There may be some side effects if the injection helps you produce ePO a reagent, if we use protalyx hydroxylase inhibitors, there are now three clinical trials in progress that can be used to treat anemia in patients with chronic kidney disease.

Lack of oxygen in tumors is also a symptom of advanced cancer, which is associated with increased mortality. This picture shows the case of patients with advanced cancer, which are already apoptotic cells, brown hIF-1 alpha antibodies, we can see that there is a large number of HIF-1 alpha production here. What we know is that a lot of chemotherapy can kill such cells, but without such a treatment directly targeting the cell, the drug we are developing may help treat cancer. We have seen a number of drugs that can effectively control the growth and metastasis of primary tumors in animal models, and through the HIF-1 inhibitor Digoxin, the growth and metastasis of primary tumors in the three-negative breast cancer insitu model can be reduced, so it has a therapeutic effect on cancer.

Let’s make a summary. Pathways play the following roles in biology and medicine:

First, in the development process, HIF-1 alpha, HIF-1 beta, HIF-2 alpha, PHD2 and VHL are all necessary for normal embryo development in mammals.

Second, for physiology, even a small increase or loss of pathway component function can interfere with the normal post-birth response to hypoxia physiology.

Third, for those in Tibet and the Andean highlands, genetic evidence suggests that these and other species have been able to successfully adapt to key genetic targets at high altitudes, thanks to homologous genes of HIF-1 alpha, HIF-1 beta, PHD and VHL.

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