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Your report will have Your name, title, abstract (300 to 500 words), introduction (why is it important and focus), key information (figures, illustrations, data), discussion, information sites and publications.2)I have an outlined what information that will be included for both the hormone and receptor(s) to complete report. This includeskey information that can be conveyed as text, figures, illustrations or tables. I find organizing information is easiest withPPT. You can submit-upload the final report as PowerPoint or Word doc. If you are using Google Docs there will be a place for a URL link.3)I have included trusted online information sites that are appropriate for the report: A) Wikipedia;B) PubMed; C) NIH/Protein; D) Google Images; E) KEGG Pathways; F) MedlinePlus; G) Mayo Clinic and other sites.4)In addition, at least 5 scientific references from PubMed will be included. You should download free PDF copies of the articles,read them and include the first page (PDF) in your reports.5)By reviewing this information and literature you will select the final emphasis of your hormone report. 6)I anticipate each report will be between 12 to 25 pages. There will be a CANVAS module set up for submission.
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Running Head: HORMONE REPORT
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Report about Erythropoietin Hormone and Receptors
Name
Institutional Affiliation
Course
Date
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Abstract
This report explores how hormones, neurotransmitters, and neurohormones released by
the human body, regulate and coordinate homeostatic processes. All these signaling factors are
essential for the proper physiological functioning of the human body. We will examine in detail
how target tissues respond to receptor-ligand information. We shall further look into how any
altercation of these ligands' interaction- receptors affects one's health and disease processes both
acutely and long- term. The major areas covered in this report are hormones and receptors. We
shall use an example of one hormone and receptors to explore the correlation between normal
physiological processes of the body and molecular, biochemical concepts.
The report includes well researched and evaluated concepts supported by relevant sources
that are up to date and trustworthy. These sources are mainly online information sites with
information relevant to our study. The sources used include Wikipedia, PubMed, NIH/Protein,
Medline Plus, Mayo clinic, KEGG pathways, and google images. In this case, the hormone we
will be analyzing is Erythropoietin. We will review the class to which the hormone belongs, with
the example of insulin. We shall equally examine the regulatory and homeostatic impact on an
organism's tissues and cells. We shall also use insulin receptors to analyze disorders related to
little or too much Signaling.
The report will also include charts and diagrams of the various concepts discussed. These
include those of protein sequences. There are additional images that give additional information
about erythropoietin hormone concerning protein synthesis and receptor Signaling. Additional
charts showing the expression of genes are also included in the report.
Keywords – receptors, hormones, insulin, homeostatic, physiological
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Introduction
This study's major focus is to understand in detail the concepts surrounding the
erythropoietin hormone and receptor. It is necessary to examine these two working principles
because of major homeostatic processes in the human body. It is also necessary to understand the
effect of high or low erythropoietin content in the bloodstream as it is useful in primary
regulatory body functions. This report will analyze the structure, effects, and working principles
of erythropoietin hormone and receptor.
Erythropoietin Hormone
The erythropoietin hormone is a glycoprotein cytokine predominantly secreted by
specific cells found in the kidney. Its primary purpose is to stimulate the production of sufficient
erythrocytes by the bone marrow's stem cells. It also serves to protect the red blood cells from
destruction (Mocini et al., 2007). This serves to aid in several physiological and homeostatic
functions of the body. The diagram below shows how a low red blood cell count in the body
stimulates the kidney to produce Erythropoietin hence increasing the synthesis of erythrocytes.
The cytokine erythropoietin (EPO) invigorates the production of billions of erythrocytes.
After production into the bloodstream, its primary destination is the progenitor cells of the
erythroid glands located within the bone marrow to conduct erythropoiesis, producing the
erythrocytes. EPO works to stimulate proliferation, differentiation, and cell survival by acting as
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a binder to the erythroid progenitor cells' surface receptors. Studies have shown that if a
knockout of the EPO receptor occurs, it can cause embryonic death due to severe anemia.
Homeostatic and regulatory impact on organisms
Erythropoietin (EPO) is a useful hormone for maintaining body tissues, stress response,
and metabolism. It is a hormone coded into 193 amino acid polypeptides with carboxyl-terminal
arginine and a 27 amino acid canonical leader sequence. It belongs to the hematopoietic cytokine
family and is often associated with its structural similarity to the growth hormone. Some of its
standard regulatory functions include:
•
Erythropoietin regulation in the critical liver and adult kidney
•
Use of Hypoxia-Induced Factor to regulate EPO gene expression.
EpoR is expressed in particular non-hematopoietic tissues at the peak in erythroid
progenitor cells that provide EPO responses. Non-hematopoietic expression of EpoR and the
plausible outcome of EPO activity obtained through models, including vascular endothelium to
instigate nitrogen oxide production regulating vascular tone (Zhang et al., 2014). It also
facilitates skeletal muscle myoblasts' production to promote wound healing. Moreover, it
stimulates the heart to protect against ischemic injury. All these in conjunction with EPO being a
multi-functional cytokine whose primary function is to regulate red blood cell production in the
bone marrow.
EPO is equally known for regulating inflammation. It is stimulated whenever an
inflammation occurs in the body. It acts upon the inflammation by inhibiting inflammatoryinducing cytokine production and endothelial cell response and by reducing immune cell
response to the affected area. This property comes into use for cardiovascular system treatments
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and the central nervous system. It is also applicable to the gut and liver. It is used in combination
with oral iron improved anemia to treat inflammatory bowel disease with anemia refractory.
Erythropoietin is known to minimize Insulin resistance in adipocytes. EPO being a
glycoprotein, has been widely used in treating anemia caused by tumors and chronic kidney
diseases. EPO is active in many body tissues. These include renal, endothelium, cardiovascular
tissues, nerves, and muscle tissues in response to metabolic and muscle stress. However, the role
of the hormone and its receptors in skeletal muscles have not yet been fully explained to date.
The uncertainty arises from evidence suggesting that C2C12 myoblasts, when treated with EPO,
indicate elevated JAK2, STAT5, and AKT. This similarity is associated with signaling responses
observed in neural cells.
Type two diabetic organisms can be treated with the help of Erythropoietin.
Administering EPO can reduce insulin resistance greatly and also activate its related receptor
erythropoietin receptor (EPOR). Moreover, using EPO treatment to increase glucose intolerance
in humans has proven to be a huge success (Pan et al., 2017). The study's overall result to
investigate this concept showed that EPO= EPOR treatment is beneficial to enhance glues uptake
in the body and activate downstream signaling molecules such as P13K, AKT IRS-1. And
Besides, it improves autophagy and minimizes apoptosis in skeletal muscle that is type two
diabetic.
Summary of Homeostatic and Regulatory functions of EPO
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Chemical Structure or AA sequence
As earlier mentioned, Erythropoietin (EPO) is a glycoprotein. It has over 30,400 Daltons
of glycoprotein, with 165 amino acids secreted primarily in the kidney. Some minimal contents
of EPO are produced in the liver for the purpose of erythrocytosis regulation. Its well- versed
function is acting on erythroid precursor cell at the colony-forming units-erythroid stage, thus
aiding apoptosis inhibition. EPO activates at least three specific intracellular signaling pathways
by binding on a specific membrane receptor. These intracellular pathways include Ras-mitogenactivated protein kinase, phosphatidylinositol 3-kinase/ protein kinase B, and some members of
the signal transducers and activators of the transcription family.
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The EPO gene is situated on the 7th chromosome. It is composed of four introns and five
exons, and an amino acid chain of 193 bases forms the transcriptional product of the gene. When
gene translation takes place, the chain is altered and modified to 166 amino acids. The 27 amino
acid leader sequence that has been split is mostly made of hydrophobic amino acids. The final
length of the chain is 165 amino acids. This length is achieved after translation is complete, and
the C-terminus has lost its final arginine residue. The total weight of the glycoprotein is 30 kDa,
with the peptide backbone weighing 18 kDa. EPO, as a glycoprotein, contains sulfur content in
its structural composition. This sulfur of the cysteine residues combines to form disulfide bonds
that help maintain the EPO's structure. The EPO's structure comprises four alpha helixes, namely
A to D. These helixes are interconnected one to another, thus forming the normal EPO structure.
Structure of Erythropoietin with 165 Amino Acids
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Amino acid substitutions in the extracellular domain of the human EPO receptor
KEGG Pathway for cytokine to cytokine receptor interaction
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Synthesis
Under normal conditions, in the absence of anemia, Erythropoietin levels in the blood are
quite low. The volume of EPO content in the blood is around ten mU/mL. However, when the
oxygen reaching body tissues reduces, and hypoxia occurs, EPO production can rise to about
10 000 mU/mL in blood. In adults, the organs responsible for the synthesis of EPO are the
interstitial cells in the renal cavity's peritubular capillary bed (Pan et al., 2017). Nevertheless,
studies have shown evidence of additional amounts being produced by the brain and the liver.
The dimeric protein complex in charge of how the body responds to low oxygen concentration is
called the Hypoxia- Inducible Factor (Mocini et al., 2007). They are the transcription factors for
EPO and are proteasomal and hydroxylated digested in oxygen and iron. Gata2 inhibits the
promoter region for EPO during normoxia. But during hypoxia, the levels decrease during and
give room for the promotion of EPO production. According to medical health researchers,
regulation of EPO amounts synthesized relies on a feedback mechanism that measures iron and
oxygenated blood availability.
Stages of erythroid differentiation and oxygen-dependent feedback loop regulated
by kidney EPO
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Type of Functional Endocrine signal
Erythropoietin (EPO) has similar functionality as a regular endocrine hormone. This is
because it affects target cells in the bone marrow by interacting with specific cell-surface
receptors. In this case, the cell surface receptor consists of two EPOR molecules.
Erythropoietin Receptor
The receptor discussed in this report is the erythropoietin receptor (EpoR). The EpoR is
located on the erythroid progenitor cells. It is a protein in the human body encoded by
the EPOR gene. It belongs to the family of cytokine receptors and pre-exists as dimers. When
bound with a 30 kDa ligand erythropoietin (EPO), they change their homodimerized state. EpoR
has a single carbohydrate chain and is a peptide. It contributes to approximately 56-57 kDa of the
protein found on EPO responding cells' surface. When the homodimerized state changes, Jak2
kinases are autophosphorylated. The receptor depends on these Jak2 kinases for all their intrinsic
kinase activity as it does not possess its own.
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The known function of EpoR is to prevent apoptosis by attaching to the EPO. It
achieves this by promoting proliferation and rescue of erythroid progenitors. However, vitro
rescue experiments have revealed that the determined three-dimensional structure of the EPOR
can cause dimerization of the EPOR domain together with a biologically active 20 amino acid
peptide. EPO activates the JAK2-STAT5 pathway and two tyrosine residues in the cytoplasmic
domain of EPOR, which are necessary to activate STAT5. The physiologic role of STAT5 in
erythroid cell proliferation and differentiation is still subject to debate among many scientists to
date.
Structure of the erythropoietin receptor
The Erythropoietin belongs to the class I cytokine receptor. It forms a complex structure
that is homodimeric, heterodimeric, or heterotrimeric containing a WSXWS motif in the
extracellular domain. It also has a single transmembrane domain. It is the homodimeric receptor
complex to which the EPO binds, thus bringing the JAK2 kinases closer to allow JAK
phosphorylation of the receptor, transphosphorylation, and phosphorylation and activation of
STAT and other downstream signaling pathways.
The diagram below shows the Erythropoietin receptor and signaling pathways. It has
clearly outlined the structure of the receptor dimer. The various docking sites for several
intracellular proteins have been marked with P and linked with the black-dotted arrow to
individual pathway components. Positive interactions are presented with full black arrows and
negative interactions with dotted red.
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Signal Transduction pathways
Signal transduction via the erythropoietin receptor is initiated by ligand binding, which
causes the dimerization of EPOR monomers. The EpoR activates the activator of transcription
(STAT) pathway and the Janus-activated kinase (JAK). The kinase that the EpoR predominantly
associates with is the JKA2. It serves as a protein transporter for the EpoR to the endoplasmic
reticulum’s plasma membrane.
Multiple signaling pathw...