Hutchinson Gilford Progeria Syndrome Research Paper
Abstract Hutchinson–Gilford progeria syndrome is an extreme rare genetic disorder that catastrophically influences children in pre-mature aging and dying in their teenagers. So far, all drugs used to treat this disease are focusing on reducing complications and extending the life spans of patients, but no treatment has been proven to treat this disease directly and effectively. Fortunately, the new drug named farnesyltransferase inhibitors appears recently in the research field of Hutchinson–Gilford progeria. My hypothesis is that farnesyltransferase inhibitors are effective and safe to treat children born with progeria. My first objective is to test the effectiveness of farnesyltransferase inhibitors in both animal and human models.
…show more content…
My second objective is to test the safety of farnesyltransferase inhibitors usage, especially focusing on whether the treatment causes toxicity. My research is very significant and meaningful because the research and development of new drug will not only benefit children born with progeria and save their lives, but also provides better understanding in human aging processes.
Specific Aims Recently, farnesyltransferase inhibitors become a hot topic in the research field of Hutchinson–Gilford progeria syndrome. I hypothesize that farnesyltransferase inhibitors are effective and safe to treat children born with progeria directly. My aims are to test the effectiveness this drug in both animal models and human cells, and safety (toxicity) in C. elegans.
1. Test the effectiveness of farnesyltransferase inhibitors. The goal of this part is to test whether farnesyltransferase inhibitors is helpful to reduce the percentage of abnormal shaped nuclear envelopes by preventing the accumulation of prelamin A progerin. The question can be answered by comparing the percentage of normal shaped nuclear envelopes in HGPS sample and in HGPS treated by farnesyltransferase inhibitors.
2. Test the safety (toxicity) of farnesyltransferase inhibitors treatments. The C. elegans growth assays will be used to test the toxicity of farnesyltransferase inhibitors treatments. The basic idea is that C. elegans are fed by farnesyltransferase inhibitors. Several observations on C. elegans are obtained, including neuronal development using GFP-labeled neurons as well as their body growth and development. (Boyd 2012) According to the effects of farnesyltransferase inhibitors on C. elegans, the toxicity of this drug can be exploited and answered.
Background and Significance Hutchinson–Gilford progeria syndrome, short for HGPS and known as progeria, is an extremely rare genetic disorder which has an extremely low incidence rate and occurs in 1 per 8 million live births. Progeria has extreme negative effects on children, causing them to premature aging and die in their teenagers. Commonly, children born with progeria live to no more than twenty years old and do not reach reproduction years, so this syndrome is hardly inherited. The symptoms of progeria disorder are very obvious from birth of children to their childhood, including failure to thrive, localized scleroderma-like skin, limited growth, full-body alopecia, wrinkled skin, and etc. Later, some other complications are caused due to progeria disorder, such as cardiovascular, loss of eyesight and kidney dysfunctions. (Deepu 2015) It is well accepted that most HGPS are caused by a point mutation (cytosine replacing thymine at position 608 within exon 11) of LMNA gene, coding for prelamin A protein. The formation of mutated lamin A has strong connection with the farnesyl function group. Farnesyl groups will never be removed from prelamin A and their staying results in an abnormal short mRNA transcript, finally leading to the formation of a dominant negative lamin A. (Mcclintock 2007) There are two possible mechanisms to explain the relationship between lumin A mutation and related genetic disorders. One possible reason is that it is the mutation of lumin A that weakens the lamina, so that the nucleus becomes vulnerable to mechanical forces. As a consequence, the genome inside the nucleus might be attacked and damaged. Another explanation is that lamin proteins might lose their ability to organize the genome, so genes might posit in wrong places. Wrong position of gene leads to the disruption of normal functions. (Misteli 2011) Except observing symptoms of children, a genetic test on LMNA gene can further confirm the diagnosis of the disorder. (Deepu 2015) Studying Hutchinson–Gilford progeria syndrome is meaningful and significant not only to the patients but also for the whole society.
On the one hand, figuring out causes, mechanisms, and possible treatments, specifically farnesyltransferase inhibitors, will be a huge success and even a milestone in the clinical medicine. It will benefit children born with this genetic disorder. On the other hand, besides studying the disorder itself, scientists can find out some clues and hints about the normal aging process. It will be advantages for the whole human being to know their aging process. (Deepu 2015) So far, there is no treatment proven effective and curable for this disorder. The most common treatments aim at elongating children’s lives and reducing complications, such as cardiovascular diseases. Some medicines are suggested to prevent heart attacks and some high-nutrition supplements are recommended to prevent weight loss. Recently, scientists find a new drug called farnesyltransferase inhibitor that might be used to treat HGPS in the future. However, the effectiveness and safety of farnesyltransferase inhibitor are not well studied so far. Based on these unsolved problems, the objective of this mini grant proposal is to try to access the effectiveness and safety of farnesyltransferase inhibitors in both animal models and human cells. (Deepu
2015)
My second objective is to test the safety of farnesyltransferase inhibitors usage, especially focusing on whether the treatment causes toxicity. My research is very significant and meaningful because the research and development of new drug will not only benefit children born with progeria and save their lives, but also provides better understanding in human aging processes.
Specific Aims Recently, farnesyltransferase inhibitors become a hot topic in the research field of Hutchinson–Gilford progeria syndrome. I hypothesize that farnesyltransferase inhibitors are effective and safe to treat children born with progeria directly. My aims are to test the effectiveness this drug in both animal models and human cells, and safety (toxicity) in C. elegans.
1. Test the effectiveness of farnesyltransferase inhibitors. The goal of this part is to test whether farnesyltransferase inhibitors is helpful to reduce the percentage of abnormal shaped nuclear envelopes by preventing the accumulation of prelamin A progerin. The question can be answered by comparing the percentage of normal shaped nuclear envelopes in HGPS sample and in HGPS treated by farnesyltransferase inhibitors.
2. Test the safety (toxicity) of farnesyltransferase inhibitors treatments. The C. elegans growth assays will be used to test the toxicity of farnesyltransferase inhibitors treatments. The basic idea is that C. elegans are fed by farnesyltransferase inhibitors. Several observations on C. elegans are obtained, including neuronal development using GFP-labeled neurons as well as their body growth and development. (Boyd 2012) According to the effects of farnesyltransferase inhibitors on C. elegans, the toxicity of this drug can be exploited and answered.
Background and Significance Hutchinson–Gilford progeria syndrome, short for HGPS and known as progeria, is an extremely rare genetic disorder which has an extremely low incidence rate and occurs in 1 per 8 million live births. Progeria has extreme negative effects on children, causing them to premature aging and die in their teenagers. Commonly, children born with progeria live to no more than twenty years old and do not reach reproduction years, so this syndrome is hardly inherited. The symptoms of progeria disorder are very obvious from birth of children to their childhood, including failure to thrive, localized scleroderma-like skin, limited growth, full-body alopecia, wrinkled skin, and etc. Later, some other complications are caused due to progeria disorder, such as cardiovascular, loss of eyesight and kidney dysfunctions. (Deepu 2015) It is well accepted that most HGPS are caused by a point mutation (cytosine replacing thymine at position 608 within exon 11) of LMNA gene, coding for prelamin A protein. The formation of mutated lamin A has strong connection with the farnesyl function group. Farnesyl groups will never be removed from prelamin A and their staying results in an abnormal short mRNA transcript, finally leading to the formation of a dominant negative lamin A. (Mcclintock 2007) There are two possible mechanisms to explain the relationship between lumin A mutation and related genetic disorders. One possible reason is that it is the mutation of lumin A that weakens the lamina, so that the nucleus becomes vulnerable to mechanical forces. As a consequence, the genome inside the nucleus might be attacked and damaged. Another explanation is that lamin proteins might lose their ability to organize the genome, so genes might posit in wrong places. Wrong position of gene leads to the disruption of normal functions. (Misteli 2011) Except observing symptoms of children, a genetic test on LMNA gene can further confirm the diagnosis of the disorder. (Deepu 2015) Studying Hutchinson–Gilford progeria syndrome is meaningful and significant not only to the patients but also for the whole society.
On the one hand, figuring out causes, mechanisms, and possible treatments, specifically farnesyltransferase inhibitors, will be a huge success and even a milestone in the clinical medicine. It will benefit children born with this genetic disorder. On the other hand, besides studying the disorder itself, scientists can find out some clues and hints about the normal aging process. It will be advantages for the whole human being to know their aging process. (Deepu 2015) So far, there is no treatment proven effective and curable for this disorder. The most common treatments aim at elongating children’s lives and reducing complications, such as cardiovascular diseases. Some medicines are suggested to prevent heart attacks and some high-nutrition supplements are recommended to prevent weight loss. Recently, scientists find a new drug called farnesyltransferase inhibitor that might be used to treat HGPS in the future. However, the effectiveness and safety of farnesyltransferase inhibitor are not well studied so far. Based on these unsolved problems, the objective of this mini grant proposal is to try to access the effectiveness and safety of farnesyltransferase inhibitors in both animal models and human cells. (Deepu
2015)