Future Directions
Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive trait classified by the inability to feel pain and temperature as well as having a reduction or complete absence of sweating. The inability to feel pain and temperature leads to self mutilation and unintentional injuries. Common forms of self mutilation include biting of the tongue, lips or fingers. Anhidrosis prevents patients from being able to sweat, which prevents the patients from regulating their body temperature. Being unable to regulate their body temperature leads to high fevers and seizures. [1]
CIPA is caused by a mutation in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). The NTRK1 protein is an enzyme that changes the activity of other proteins by adding a cluster of oxygen or phosphorus atoms at specific positions, which is know as phosphorylation. The NTRK1 protein is activated when a nerve growth factor beta (NGFβ) binds to it and signals the NTRK1 protein to phosphorylate itself. Many of the NTRK1 gene mutations lead to the production of a NTRK1 protein that cannot be activated by phosphorylation. When the NTRK1 protein fails to be activated by phosphorylation it is unable to transmit growth and survival signals to the neurons. Without signals from the NTRK1 protein the neurons die by a process of self destruction (apoptosis). People with CIPA lose the ability to feel pain due to the loss of these sensory neurons. Some people with CIPA also lose the nerves leading to their sweat glands, which causes anhidrosis [2]
Mice were selected as an ideal model organism because of the well conserved tyrosine kinase domain found in both humans and mice. In mice, homozygous null mutations in the NTRK1 gene results in premature death due to severe sensory and sympathetic neuropathies. [3]
Nerve Growth Factor (NGF) was discovered in the NTRK1 interaction network. NGF is a small secreted protein that is important for the growth, maintenance and survival of sensory neurons. NGF stimulates the division and differentiation of sympathetic and embryonic sensory neurons. [4] Research has shown an over expression of NGF and NTRK1 in the intra-epidermal nerve fibers in diabetic rat skin. [5]
The discovery of this information led to the formulation of the question "What is the Connection between CIPA and diabetic patients?" CIPA patients have decreased expression levels of NTRK1 and have the inability to feel pain, while diabetic patients have an increased expression of NTRK1 and have lots of pain.
Diabetic neuropathy is a nerve disorder caused by diabetes, which can lead to nerve damage throughout the body. Diabetic neuropathy is associated with pain, tingling or numbness in the hands, feet, arms and legs. Peripheral neuropathy is the most common form the symptoms include insensitivity to pain or temperature. There is no treatment for diabetic neuropathy, but controlling blood glucose levels and medications can be used to reduce symptoms or decrease the associated pain. [6] Learning about diabetic neuropathy led to the question of "Why do nerves degenerate in diabetic patients?"
Returning to the NTRK1 protein interaction network sequestosome 1 (SQSTM1) was identified as a protein that binds ubiquitin and may regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. SQSTM1 is believed to be involved in cell differentiation, apoptosis, immune response and the regulation of K(+) channels. [4] Apoptosis is the process of programmed cell death.
The first proposed experiment is to preform a micro array to determine "Is SQSTM1 highly expressed in diabetic patients?" Based on the over expression of NGF and NTRK1, SQSTM1 is likely to also be over expressed in diabetic patients. With the over expression of SQSTM1, apoptosis is more likely to occur, which may explain why the nerves in diabetic patients degenerate.
The second proposed experiment involves using chemical genetics to determine "Can NGF, NTRK1 and SQSTM1 be modulated in diabetic patients so the pain goes away?" The hypothesis is genes that are unregulated in diabetic patients cause pain, regulation of these genes using a small molecule would alleviate pain. Using a chemical genetics screen is proposed to discover new compounds that bind to SQSTM1. A few small molecules have been discovered that reduce expression of NGF [7]. Are these small molecules also capable of reducing the expression of NTRK1 and SQSTM1 in diabetic patients? Lowering the expression of one gene may be able to lower the expression of other genes in the protein interaction network.
The experiments proposed have potential drug therapy implications for diabetic neuropathy. The research would also increase our understanding of CIPA, Diabetic neuropathy and the gene SQSTM1.
CIPA is caused by a mutation in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). The NTRK1 protein is an enzyme that changes the activity of other proteins by adding a cluster of oxygen or phosphorus atoms at specific positions, which is know as phosphorylation. The NTRK1 protein is activated when a nerve growth factor beta (NGFβ) binds to it and signals the NTRK1 protein to phosphorylate itself. Many of the NTRK1 gene mutations lead to the production of a NTRK1 protein that cannot be activated by phosphorylation. When the NTRK1 protein fails to be activated by phosphorylation it is unable to transmit growth and survival signals to the neurons. Without signals from the NTRK1 protein the neurons die by a process of self destruction (apoptosis). People with CIPA lose the ability to feel pain due to the loss of these sensory neurons. Some people with CIPA also lose the nerves leading to their sweat glands, which causes anhidrosis [2]
Mice were selected as an ideal model organism because of the well conserved tyrosine kinase domain found in both humans and mice. In mice, homozygous null mutations in the NTRK1 gene results in premature death due to severe sensory and sympathetic neuropathies. [3]
Nerve Growth Factor (NGF) was discovered in the NTRK1 interaction network. NGF is a small secreted protein that is important for the growth, maintenance and survival of sensory neurons. NGF stimulates the division and differentiation of sympathetic and embryonic sensory neurons. [4] Research has shown an over expression of NGF and NTRK1 in the intra-epidermal nerve fibers in diabetic rat skin. [5]
The discovery of this information led to the formulation of the question "What is the Connection between CIPA and diabetic patients?" CIPA patients have decreased expression levels of NTRK1 and have the inability to feel pain, while diabetic patients have an increased expression of NTRK1 and have lots of pain.
Diabetic neuropathy is a nerve disorder caused by diabetes, which can lead to nerve damage throughout the body. Diabetic neuropathy is associated with pain, tingling or numbness in the hands, feet, arms and legs. Peripheral neuropathy is the most common form the symptoms include insensitivity to pain or temperature. There is no treatment for diabetic neuropathy, but controlling blood glucose levels and medications can be used to reduce symptoms or decrease the associated pain. [6] Learning about diabetic neuropathy led to the question of "Why do nerves degenerate in diabetic patients?"
Returning to the NTRK1 protein interaction network sequestosome 1 (SQSTM1) was identified as a protein that binds ubiquitin and may regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. SQSTM1 is believed to be involved in cell differentiation, apoptosis, immune response and the regulation of K(+) channels. [4] Apoptosis is the process of programmed cell death.
The first proposed experiment is to preform a micro array to determine "Is SQSTM1 highly expressed in diabetic patients?" Based on the over expression of NGF and NTRK1, SQSTM1 is likely to also be over expressed in diabetic patients. With the over expression of SQSTM1, apoptosis is more likely to occur, which may explain why the nerves in diabetic patients degenerate.
The second proposed experiment involves using chemical genetics to determine "Can NGF, NTRK1 and SQSTM1 be modulated in diabetic patients so the pain goes away?" The hypothesis is genes that are unregulated in diabetic patients cause pain, regulation of these genes using a small molecule would alleviate pain. Using a chemical genetics screen is proposed to discover new compounds that bind to SQSTM1. A few small molecules have been discovered that reduce expression of NGF [7]. Are these small molecules also capable of reducing the expression of NTRK1 and SQSTM1 in diabetic patients? Lowering the expression of one gene may be able to lower the expression of other genes in the protein interaction network.
The experiments proposed have potential drug therapy implications for diabetic neuropathy. The research would also increase our understanding of CIPA, Diabetic neuropathy and the gene SQSTM1.
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References
[1] "Congenital Insensitivity to Pain with Anhidrosis." CIPA. U.S. National Library of Medicine, 28 Jan. 2013. Web. 04 Feb. 2013. <http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain-with-anhidrosis>.
[2] "NTRK1." - Neurotrophic Tyrosine Kinase, Receptor, Type 1. U.S. National Library of Medicine, 28 Jan. 2013. Web. 04 Feb. 2013. <http://ghr.nlm.nih.gov/gene/NTRK1>.
[3] Ntrk1 MGI Mouse Gene Detail - MGI:97383 - Neurotrophic Tyrosine Kinase, Receptor, Type 1." Ntrk1 MGI Mouse Gene Detail - MGI:97383 - Neurotrophic Tyrosine Kinase, Receptor, Type 1. Mouse Genome Database, 1 May 2013. Web. 15 May 2013.
[4] http://string-db.org/
[5] Evans, Laura. "Increased Cutaneous NGF and CGRP-labelled TrkA-positive Intra-epidermal Nerve Fibres in Rat Diabetic Skin." Neuroscience Letters 506.1 (2012): 59-63. Print.
[6] "National Diabetes InformationClearinghouse (NDIC)." Diabetic Neuropathies: The Nerve Damage of Diabetes. National Diabetes Information Clearinghouse (NDIC), 25 June 2012. Web. 15 May 2013.
[7] Eibl, Joseph. "Identification of Novel Pyrazoloquinazolinecarboxilate Analogues to Inhibit Nerve Growth Factor in Vitro." European Journal of Pharmacology 708.1-3 (2013): 30-37. Print.
[2] "NTRK1." - Neurotrophic Tyrosine Kinase, Receptor, Type 1. U.S. National Library of Medicine, 28 Jan. 2013. Web. 04 Feb. 2013. <http://ghr.nlm.nih.gov/gene/NTRK1>.
[3] Ntrk1 MGI Mouse Gene Detail - MGI:97383 - Neurotrophic Tyrosine Kinase, Receptor, Type 1." Ntrk1 MGI Mouse Gene Detail - MGI:97383 - Neurotrophic Tyrosine Kinase, Receptor, Type 1. Mouse Genome Database, 1 May 2013. Web. 15 May 2013.
[4] http://string-db.org/
[5] Evans, Laura. "Increased Cutaneous NGF and CGRP-labelled TrkA-positive Intra-epidermal Nerve Fibres in Rat Diabetic Skin." Neuroscience Letters 506.1 (2012): 59-63. Print.
[6] "National Diabetes InformationClearinghouse (NDIC)." Diabetic Neuropathies: The Nerve Damage of Diabetes. National Diabetes Information Clearinghouse (NDIC), 25 June 2012. Web. 15 May 2013.
[7] Eibl, Joseph. "Identification of Novel Pyrazoloquinazolinecarboxilate Analogues to Inhibit Nerve Growth Factor in Vitro." European Journal of Pharmacology 708.1-3 (2013): 30-37. Print.