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HUMAN Brain Anatomy

 

What is the brain?

The brain is a complex organ that controls thought, memory, emotion, touch, motor skills, vision, breathing, temperature, hunger and every process that regulates our body. Together, the brain and spinal cord that extends from it make up the central nervous system, or CNS.

What is the brain made of?

Weighing about 3 pounds in the average adult, the brain is about 60% fat. The remaining 40% is a combination of water, protein, carbohydrates and salts. The brain itself is  not a muscle. It contains blood vessels and nerves, including neurons and glial cells.

What is the gray matter and white matter?

Gray and white matter are two different regions of the central nervous system. In the brain, gray matter refers to the darker, outer portion, while white matter describes the lighter, inner section underneath. In the spinal cord, this order is reversed:

    The white matter is on the outside, and the gray matter sits within.

Gray matter is primarily composed of neuron somas (the round central cell bodies), and white matter is mostly made of axons (the long stems that connects neurons together) wrapped in myelin (a protective coating). The different composition of neuron parts is why the two appear as separate shades on certain scans

 

Brain of a human embryo in the sixth week of development

                      Motor and sensory regions of the brain

Each region serves a different role. Gray matter is primarily responsible for processing and interpreting information, while white matter transmits that information to other parts of the nervous system.

 

How does the brain work?

The brain sends and receives chemical and electrical signals throughout the body. Different signals control different processes, and your brain interprets each. Some make you feel tired, for example, while others make you feel pain.

Some messages are kept within the brain, while others are relayed through the spine and across the body’s vast network of nerves to distant extremities. To do this, the central nervous system relies on billions of neurons (nerve cells).

Main Parts of the Brain and Their Functions

At a high level, the brain can be divided into the cerebrum, brainstem and cerebellum.

Cerebrum

The cerebrum (front of brain) comprises gray matter (the cerebral cortex) and white matter at its center. The largest part of the brain, the cerebrum initiates and coordinates movement and regulates temperature. Other areas of the cerebrum enable speech, judgment, thinking and reasoning, problem-solving, emotions and learning. Other functions relate to vision, hearing, touch and other senses.

Cerebral Cortex

Cortex is Latin for “bark,” and describes the outer gray matter covering of the cerebrum. The cortex has a large surface area due to its folds, and comprises about half of the brain’s weight.

The cerebral cortex is divided into two halves, or hemispheres. It is covered with ridges (gyri) and folds (sulci). The two halves join at a large, deep sulcus (the interhemispheric fissure, AKA the medial longitudinal fissure) that runs from the front of the head to the back. The right hemisphere controls the left side of the body, and the left half controls the right side of the body. The two halves communicate with one another through a large, C-shaped structure of white matter and nerve pathways called the corpus callosum. The corpus callosum is in the center of the cerebrum.

Brainstem

The brainstem (middle of brain) connects the cerebrum with the spinal cord. The brainstem includes the midbrain, the pons and the medulla.

• Midbrain. The midbrain (or mesencephalon) is a very complex structure with a range of different neuron clusters (nuclei and colliculi), neural pathways and other structures. These features facilitate various functions, from hearing and movement to calculating responses and environmental changes. The midbrain also contains the substantia nigra, an area affected by Parkinson’s disease that is rich in dopamine neurons and part of the basal ganglia, which enables movement and coordination.
• Pons. The pons is the origin for four of the 12 cranial nerves, which enable a range of activities such as tear production, chewing, blinking, focusing vision, balance, hearing and facial expression. Named for the Latin word for “bridge,” the pons is the connection between the midbrain and the medulla.
• Medulla. At the bottom of the brainstem, the medulla is where the brain meets the spinal cord. The medulla is essential to survival. Functions of the medulla regulate many bodily activities, including heart rhythm, breathing, blood flow, and oxygen and carbon dioxide levels. The medulla produces reflexive activities such as sneezing, vomiting, coughing and swallowing.

The spinal cord extends from the bottom of the medulla and through a large opening in the bottom of the skull. Supported by the vertebrae, the spinal cord carries messages to and from the brain and the rest of the body.

Cerebellum

The cerebellum (“little brain”) is a fist-sized portion of the brain located at the back of the head, below the temporal and occipital lobes and above the brainstem. Like the cerebral cortex, it has two hemispheres. The outer portion contains neurons, and the inner area communicates with the cerebral cortex. Its function is to coordinate voluntary muscle movements and to maintain posture, balance and equilibrium. New studies are exploring the cerebellum’s roles in thought, emotions and social behavior, as well as its possible involvement in addiction, autism and schizophrenia.

Brain Coverings: Meninges

Three layers of protective covering called meninges surround the brain and the spinal cord.

• The outermost layer, the dura mater, is thick and tough. It includes two layers: The periosteal layer of the dura mater lines the inner dome of the skull (cranium) and the meningeal layer is below that. Spaces between the layers allow for the passage of veins and arteries that supply blood flow to the brain.
• The arachnoid mater is a thin, weblike layer of connective tissue that does not contain nerves or blood vessels. Below the arachnoid mater is the cerebrospinal fluid, or CSF. This fluid cushions the entire central nervous system (brain and spinal cord) and continually circulates around these structures to remove impurities.
• The pia mater is a thin membrane that hugs the surface of the brain and follows its contours. The pia mater is rich with veins and arteries.

 

Lobes of the Brain and What They Control

Each brain hemisphere (parts of the cerebrum) has four sections, called lobes: frontal, parietal, temporal and occipital. Each lobe controls specific functions.

 

        

• Frontal lobe. The largest lobe of the brain, located in the front of the head, the frontal lobe is involved in personality characteristics, decision-making and movement. Recognition of smell usually involves parts of the frontal lobe. The frontal lobe contains Broca’s area, which is associated with speech ability.
• Parietal lobe. The middle part of the brain, the parietal lobe helps a person identify objects and understand spatial relationships (where one’s body is compared with objects around the person). The parietal lobe is also involved in interpreting pain and touch in the body. The parietal lobe houses Wernicke’s area, which helps the brain understand spoken language.
• Occipital lobe. The occipital lobe is the back part of the brain that is involved with vision.
• Temporal lobe. The sides of the brain, temporal lobes are involved in short-term memory, speech, musical rhythm and some degree of smell recognition.

Deeper Structures Within the Brain

Pituitary Gland

Sometimes called the “master gland,” the pituitary gland is a pea-sized structure found deep in the brain behind the bridge of the nose. The pituitary gland governs the function of other glands in the body, regulating the flow of hormones from the thyroid, adrenals, ovaries and testicles. It receives chemical signals from the hypothalamus through its stalk and blood supply.

Hypothalamus

The hypothalamus is located above the pituitary gland and sends it chemical messages that control its function. It regulates body temperature, synchronizes sleep patterns, controls hunger and thirst and also plays a role in some aspects of memory and emotion.

Amygdala

Small, almond-shaped structures, an amygdala is located under each half (hemisphere) of the brain. Included in the limbic system, the amygdalae regulate emotion and memory and are associated with the brain’s reward system, stress, and the “fight or flight” response when someone perceives a threat.

Hippocampus

A curved seahorse-shaped organ on the underside of each temporal lobe, the hippocampus is part of a larger structure called the hippocampal formation. It supports memory, learning, navigation and perception of space. It receives information from the cerebral cortex and may play a role in Alzheimer’s disease.

Pineal Gland

The pineal gland is located deep in the brain and attached by a stalk to the top of the third ventricle. The pineal gland responds to light and dark and secretes melatonin, which regulates circadian rhythms and the sleep-wake cycle.

Ventricles and Cerebrospinal Fluid

Deep in the brain are four open areas with passageways between them. They also open into the central spinal canal and the area beneath arachnoid layer of the meninges.

The ventricles manufacture cerebrospinal fluid, or CSF, a watery fluid that circulates in and around the ventricles and the spinal cord, and between the meninges. CSF surrounds and cushions the spinal cord and brain, washes out waste and impurities, and delivers nutrients.

Blood Supply to the Brain

Two sets of blood vessels supply blood and oxygen to the brain: the vertebral arteries and the carotid arteries.

The external carotid arteries extend up the sides of your neck, and are where you can feel your pulse when you touch the area with your fingertips. The internal carotid arteries branch into the skull and circulate blood to the front part of the brain.

The vertebral arteries follow the spinal column into the skull, where they join together at the brainstem and form the basilar artery, which supplies blood to the rear portions of the brain.

The circle of Willis, a loop of blood vessels near the bottom of the brain that connects major arteries, circulates blood from the front of the brain to the back and helps the arterial systems communicate with one another.

Cranial Nerves

Inside the cranium (the dome of the skull), there are 12 nerves, called cranial nerves:

• Cranial nerve 1: The first is the olfactory nerve, which allows for your sense of smell.
• Cranial nerve 2: The optic nerve governs eyesight.
• Cranial nerve 3: The oculomotor nerve controls pupil response and other motions of the eye, and branches out from the area in the brainstem where the midbrain meets the pons.
• Cranial nerve 4: The trochlear nerve controls muscles in the eye. It emerges from the back of the midbrain part of the brainstem.
• Cranial nerve 5: The trigeminal nerve is the largest and most complex of the cranial nerves, with both sensory and motor function. It originates from the pons and conveys sensation from the scalp, teeth, jaw, sinuses, parts of the mouth and face to the brain, allows the function of chewing muscles, and much more.
• Cranial nerve 6: The abducens nerve innervates some of the muscles in the eye.
• Cranial nerve 7: The facial nerve supports face movement, taste, glandular and other functions.
• Cranial nerve 8: The vestibulocochlear nerve facilitates balance and hearing.
• Cranial nerve 9: The glossopharyngeal nerve allows taste, ear and throat movement, and has many more functions.
• Cranial nerve 10: The vagus nerve allows sensation around the ear and the digestive system and controls motor activity in the heart, throat and digestive system.
• Cranial nerve 11: The accessory nerve innervates specific muscles in the head, neck and shoulder.
• Cranial nerve 12: The hypoglossal nerve supplies motor activity to the tongue.

The first two nerves originate in the cerebrum, and the remaining 10 cranial nerves emerge from the brainstem, which has three parts: the midbrain, the pons and the medulla.

        

Cancer Therapy by Immune checkpoint

 

                              Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor cells 2018 Nobel Laureates   James P. Allison and Tasuku Honjo  have established an entirely new principle for cancer therapy.

James P. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a brand new approach for treating patients.

                         In parallel, Tasuku Honjo discovered a protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer.

                              Allison and Honjo showed how different strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer. The seminal discoveries by the two Laureates constitute a landmark in our fight against cancer.

                                    Cancer comprises many different diseases, all characterized by uncontrolled proliferation of abnormal cells with capacity for spread to healthy organs and tissues. A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchings, 1988), and bone marrow transplantation for leukemia (Thomas 1990). However, advanced cancer remains immensely difficult to treat, and novel therapeutic strategies are desperately needed.

                          In the late 19th century and beginning of the 20th century the concept emerged that activation of the immune system might be a strategy for attacking tumor cells. Attempts were made to infect patients with bacteria to activate the defense. These efforts only had modest effects, but a variant of this strategy is used today in the treatment of bladder cancer. It was realized that more knowledge was needed. Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. Despite remarkable scientific progress, attempts to develop generalizable new strategies against cancer proved difficult.

Accelerators and brakes in our immune system

                                                The fundamental property of our immune system is the ability to discriminate “self” from “non-self” so that invading bacteria, viruses and other dangers can be attacked and eliminated. T cells, a type of white blood cell, are key players in this defense. T cells were shown to have receptors that bind to structures recognized as non-self and such interactions trigger the immune system to engage in defense. But additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T cells, inhibiting immune activation. This intricate balance between accelerators and brakes is essential for tight control. It ensures that the immune system is sufficiently engaged in attack against foreign microorganisms while avoiding the excessive activation that can lead to autoimmune destruction of healthy cells and tissues.

A new principle for immune therapy

                                        During the 1990s, in his laboratory at the University of California, Berkeley, James P. Allison studied the T-cell protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. Other research teams exploited the mechanism as a target in the treatment of autoimmune disease. Allison, however, had an entirely different idea. He had already developed an antibody that could bind to CTLA-4 and block its function . He now set out to investigate if CTLA-4 blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells.

                  The results were spectacular. Mice with cancer had been cured by treatment with the antibodies that inhibit the brake and unlock antitumor T-cell activity. Despite little interest from the pharmaceutical industry, Allison continued his intense efforts to develop the strategy into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma, a type of skin cancer. In several patients signs of remaining cancer disappeared. Such remarkable results had never been seen before in this patient group.

Discovery of PD-1 and its importance for cancer therapy

                                              In 1992, a few years before Allison’s discovery, Tasuku Honjo discovered PD-1, another protein expressed on the surface of T-cells. Determined to unravel its role, he meticulously explored its function in a series of elegant experiments performed over many years in his laboratory at Kyoto University. The results showed that PD-1, similar to CTLA-4, functions as a T-cell brake, but operates by a different mechanism. In animal experiments, PD-1 blockade was also shown to be a promising strategy in the fight against cancer, as demonstrated by Honjo and other groups. This paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer. Results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable.

Immune checkpoint therapy for cancer today and in the future

                                      After the initial studies showing the effects of CTLA-4 and PD-1 blockade, the clinical development has been dramatic. We now know that the treatment, often referred to as “immune checkpoint therapy”, has fundamentally changed the outcome for certain groups of patients with advanced cancer. Similar to other cancer therapies, adverse side effects are seen, which can be serious and even life threatening. They are caused by an overactive immune response leading to autoimmune reactions, but are usually manageable. Intense continuing research is focused on elucidating mechanisms of action, with the aim of improving therapies and reducing side effects.

                                          Of the two treatment strategies, checkpoint therapy against PD-1 has proven more effective and positive results are being observed in several types of cancer, including lung cancer, renal cancer, lymphoma and melanoma. New clinical studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma. Thus, Allison and Honjo have inspired efforts to combine different strategies to release the brakes on the immune system with the aim of eliminating tumor cells even more efficiently. A large number of checkpoint therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as targets.

Figure: Upper left: Activation of T cells requires that the T-cell receptor binds to structures on other immune cells recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA- 4 functions as a brake on T cells that inhibits the function of the accelerator. Lower left: Antibodies (green) against CTLA-4 block the function of the brake leading to activation of T cells and attack on cancer cells.Upper right: PD-1 is another T-cell brake that inhibits T-cell activation. Lower right: Antibodies against PD-1 inhibit the function of the brake leading to activation of T cells and highly efficient attack on cancer cells.

James P. Allison was born 1948 in Alice, Texas, USA. He received his PhD in 1973 at the University of Texas, Austin. From 1974-1977 he was a postdoctoral fellow at the Scripps Clinic and Research Foundation, La Jolla, California. From 1977-1984 he was a faculty member at University of Texas System Cancer Center, Smithville, Texas; from 1985-2004 at University of California, Berkeley and from 2004-2012 at Memorial Sloan-Kettering Cancer Center, New York. From 1997-2012 he was an Investigator at the Howard Hughes Medical Institute. Since 2012 he has been Professor at University of Texas MD Anderson Cancer Center, Houston, Texas and is affiliated with the Parker Institute for Cancer Immunotherapy.

Tasuku Honjo was born in 1942 in Kyoto, Japan. In 1966 he became an MD, and from 1971-1974 he was a research fellow in USA at Carnegie Institution of Washington, Baltimore and at the National Institutes of Health, Bethesda, Maryland. He received his PhD in 1975 at Kyoto University. From 1974-1979 he was a faculty member at Tokyo University and from 1979-1984 at Osaka University. Since 1984 he has been Professor at Kyoto University. He was a Faculty Dean from 1996-2000 and from 2002-2004 at Kyoto University.

How Oxygen levels affect cellular metabolism

 

                Animals need oxygen for the conversion of food into useful energy. The fundamental importance of oxygen has been understood for centuries, but how cells adapt to changes in levels of oxygen has long been unknown.

William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza discovered how cells can sense and adapt to changing oxygen availability. They identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

The seminal discoveries by 2019 Nobel Laureates revealed the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anemia, cancer and many other diseases.

Oxygen at center stage

                        Oxygen, with the formula O₂, makes up about one fifth of Earth’s atmosphere. Oxygen is essential for animal life: it is used by the mitochondria present in virtually all animal cells in order to convert food into useful energy. Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.

During evolution, mechanisms developed to ensure a sufficient supply of oxygen to tissues and cells. The carotid body, adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the blood’s oxygen levels. The 1938 Nobel Prize in Physiology or Medicine to Corneille Heymans awarded discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.

HIF (Hypoxia Inducible Factor)

In addition to the carotid body-controlled rapid adaptation to low oxygen levels (hypoxia), there are other fundamental physiological adaptations. A key physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells (erythropoiesis). The importance of hormonal control of erythropoiesis was already known at the beginning of the 20th century, but how this process was itself controlled by O₂ remained a mystery.

Gregg Semenza studied the EPO gene and how it is regulated by varying oxygen levels. By using gene-modified mice, specific DNA segments located next to the EPO gene were shown to mediate the response to hypoxia. Sir Peter Ratcliffe also studied O₂-dependent regulation of the EPO gene, and both research groups found that the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced. These were important findings showing that the mechanism was general and functional in many different cell types.

Semenza wished to identify the cellular components mediating this response. In cultured liver cells he discovered a protein complex that binds to the identified DNA segment in an oxygen-dependent manner. He called this complex the hypoxia-inducible factor (HIF) . Extensive efforts to purify the HIF complex began, and in 1995, Semenza was able to publish some of his key findings, including identification of the genes encoding HIF. HIF was found to consist of two different DNA-binding proteins, so called transcription factors, now named HIF-1α and ARNT. Now the researchers could begin solving the puzzle, allowing them to understand which additional components were involved and how the machinery works.

                                     Erythropoietin (EPO)

Erythropoietin (EPO) is a hormone produced primarily by the kidneys, with small amounts made by the liver. EPO plays a key role in the production of red blood cells (RBCs), which carry oxygen from the lungs to the rest of the body.

      The body uses a dynamic feedback system to help maintain sufficient oxygen levels and a relatively stable number of RBCs in the blood.

·         Erythropoietin is produced and released into the blood by the kidneys in response to low blood oxygen levels (hypoxemia). The amount of erythropoietin released depends on how low the oxygen level is and the ability of the kidneys to produce erythropoietin.

·         EPO is carried to the bone marrow, where it stimulates production of red blood cells. The hormone is active for a short period of time and then eliminated from the body in the urine.

·         As oxygen levels in the blood rise to normal or near normal levels, the kidneys slow production of EPO.

However, if your kidneys are damaged and do not produce enough erythropoietin, then too few RBCs are produced and you can becomes anemic. Similarly, if your bone marrow is unable to respond to the stimulation from EPO, then you may become anemic. This can occur with some bone marrow disorders or with chronic diseases, such as rheumatoid arthritis.

If you have a condition that affects the amount of oxygen you breathe in, such as a lung disease, you may produce more EPO to try to compensate for the low oxygen level. People who live at high altitudes may also have higher levels of EPO and so do chronic tobacco smokers.

If you produce too much erythropoietin, which can happen with some benign or malignant kidney tumors and with a variety of other cancers, you may produce too many RBCs (polycythemia or erythrocytosis). This can lead to an increase in the blood’s thickness (viscosity) and sometimes to high blood pressure (hypertension), blood clots (thrombosis), heart attack, or stroke. Rarely, polycythemia is caused by a bone marrow disorder called polycythemia vera, not by increased erythropoietin.

VHL: Von Hippel Lindau

When oxygen levels are high, cells contain very little HIF-1α. However, when oxygen levels are low, the amount of HIF-1α increases so that it can bind to and thus regulate the EPO gene as well as other genes with HIF-binding DNA segments (Figure 1). Several research groups showed that HIF-1α, which is normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, a cellular machine called the proteasome, recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose, degrades HIF-1α. Under such conditions a small peptide, ubiquitin, is added to the HIF-1α protein. Ubiquitin functions as a tag for proteins destined for degradation in the proteasome. How ubiquitin binds to HIF-1α in an oxygen-dependent manner remained a central question.

The answer came from an unexpected direction. At about the same time as Semenza and Ratcliffe were exploring the regulation of the EPO gene, cancer researcher William Kaelin, Jr. was researching an inherited syndrome, von Hippel-Lindau’s disease (VHL disease). This genetic disease leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. Kaelin also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia. Additional clues came from several research groups showing that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group then made a key discovery: demonstrating that VHL can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1α.

              Under normal oxygen levels, hydroxyl groups are added at two specific positions in HIF-1α . This protein modification, called prolyl hydroxylation, allows VHL to recognize and bind to HIF-1α and thus explained how normal oxygen levels control rapid HIF-1α degradation with the help of oxygen-sensitive enzymes (so-called prolyl hydroxylases). Further research by Ratcliffe and others identified the responsible prolyl hydroxylases. It was also shown that the gene activating function of HIF-1α was regulated by oxygen-dependent hydroxylation. The Nobel Laureates had now elucidated the oxygen sensing mechanism and had shown how it works.

Figure 1. When oxygen levels are low (hypoxia), HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).

Oxygen shapes physiology and pathology

Thanks to the groundbreaking work of these Nobel Laureates, we know much more about how different oxygen levels regulate fundamental physiological processes. Oxygen sensing allows cells to adapt their metabolism to low oxygen levels: for example, in our muscles during intense exercise. Other examples of adaptive processes controlled by oxygen sensing include the generation of new blood vessels and the production of red blood cells. Our immune system and many other physiological functions are also fine-tuned by the O₂-sensing machinery. Oxygen sensing has even been shown to be essential during fetal development for controlling normal blood vessel formation and placenta development.

Oxygen sensing is central to a large number of diseases . For example, patients with chronic renal failure often suffer from severe anemia due to decreased EPO expression. EPO is produced by cells in the kidney and is essential for controlling the formation of red blood cells, as explained above. Moreover, the oxygen-regulated machinery has an important role in cancer. In tumors, the oxygen-regulated machinery is utilized to stimulate blood vessel formation and reshape metabolism for effective proliferation of cancer cells. Intense ongoing efforts in academic laboratories and pharmaceutical companies are now focused on developing drugs that can interfere with different disease states by either activating, or blocking, the oxygen-sensing machinery.

Figure 2. The awarded mechanism for oxygen sensing has fundamental importance in physiology, for example for our metabolism, immune response and ability to adapt to exercise. Many pathological processes are also affected. Intensive efforts are ongoing to develop new drugs that can either inhibit or activate the oxygen-regulated machinery for treatment of anemia, cancer and other diseases.

 

Von Hippel-Lindau Syndrome

What is von Hippel-Lindau disease?

Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina. The retinal tumors are also called retinal angiomas, which can lead to blindness if not treated in a timely manner. People with VHL also have an increased risk of developing clear cell renal cell carcinoma (ccRCC), which is a specific type of kidney cancer, as well as a type of tumor in the pancreas known as pancreatic neuroendocrine tumor (pNET). Tumors of the adrenal gland or pheochromocytoma can also develop, with a small number becoming metastatic, meaning they spread to other parts of the body. 

Other features of VHL include: kidney cysts, which are closed sacs usually filled with fluid; pancreatic cysts, epididymal cystadenomas, which are tumors near a man’s testicles; broad ligament cystadenomas, which occur near the fallopian tubes in women; and endolymphatic sac tumors (ELST), which are tumors of the inner ear that may cause hearing loss.

What causes VHL?

VHL is a genetic condition. This means that the risk of developing certain types of tumors and other features of VHL can be passed from generation to generation. The gene associated with VHL is also called VHL. Inheriting a deletion or mutation (alteration) in the VHL gene gives a person an increased risk of developing any of the different signs of VHL explained above, called manifestations. Nearly everyone who has VHL syndrome has an identifiable VHL genetic mutation.

How is VHL inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. VHL follows an autosomal dominant inheritance pattern, in which inheriting 1 copy of the altered gene will likely result in a mutation of the second (normal) copy of the gene. This puts the individual at risk for developing cancer.

 

The increase in body size of humans and other vertebrates requires a

 physiological infrastructure to provide adequate delivery of oxygen to tissues

 and cells to maintain oxygen homeostasis. The heart, lungs and the vasculature

 are all part of a highly regulated system that ensures the distribution of the

 precise amount of oxygen needed throughout the mammalian organism.

1. The role of HIF-1
α pathway in cellular adaptation to hypoxic stress

Mammalian cells need to maintain proper oxygen hemostasis in order to execute their aerobic metabolism and energy generation. In cancer, heart diseases, or chronic obstructive pulmonary disorders, the cellular oxygen balance is highly impaired, and cells become hypoxic (having low oxygen (O2) levels). Hypoxia is common in many types of solid tumors, where tumor cells proliferate rapidly and form large solid tumor masses, leading to obstruction and compression of the blood vessels surrounding these masses. These abnormal blood vessels often do not function properly and result in poor O2 supply to the center tumor regions2. Tumor cells in this hypoxic region begin to adapt these low oxygen tension conditions by activating several survival pathways. Activation of HIF-1 transcription factor is the most recognized pathway adopted by hypoxic cells in this harsh microenvironment

 

 

    2. Regulation of HIF-1α pathway

The activity and accumulation of HIF-1α protein were found to be regulated at different levels throughout its life cycle inside the cells. Independently from O2 levels, HIF-1α is constitutively transcribed and synthesized through a series of signaling events involving several growth factors and other signaling molecules. HIF-1α undergoes quick degradation under normoxic conditions and normally has a very short half-life (about 5 min). In contrast, under hypoxic conditions, several pathways have been shown to control HIF-1α stability and transcriptional activity via post-transnational modifications involving hydroxylation, acetylation, ubiquitination, and phosphorylation reactions