Owais Jamil
Fall 2012
September 4, 2012
September 4, 2012
N50 RNA Pool, FasR/CD95
Nucleic Acid Aptamer Selection Against FasR for Inhibition
of Nerve Cell Apoptosis
Abstract:
Permanent damage to the nervous system can be caused by severe
physical trauma to the peripheral nervous system. Following this trauma, one of
the ways loss of function occurs is secondary damage to the central nervous
system, which occurs in the form of neuron death. If this can be prevented, victims
will be able to retain motor and cognitive ability (2).
The Fas Receptor (FasR, also known as CD95) is a member of
the tumor necrosis factor protein family that found on the surface of somatic
cells and functions in cell death. When the Fas ligand (FasL) binds to FasR, a
death inducing signaling complex (DISC) is formed (1). This triggers a
downstream signaling cascade ending with apoptosis. In nervous system
peripherals that have experienced trauma, FasR and FasL have been shown to be
present in high quantities (4).
Apoptosis is the process of programmed cell death triggered
by various signals or inducing factors. In the event of a spinal cord injury, damage
occurs at the cellular level as a result of apoptosis. In healthy nervous
systems, apoptosis pathways are used to eliminate unused neuronal connections
and eliminate damaged cells (3). However, in the case of severe trauma, cell
death can become uncontrolled, eliminating not only damaged cells but also
healthy cells (2). These damages are irreversible and can lead to severe loss
of nervous system function, and even death.
Specific Aim:
In the nervous system, when FasL binds to FasR, the DISC begins the pathway within the cell to lead to its death. To prevent this, perform the SELEX method to select an RNA aptamer with a high binding affinity for FasR. This aptamer would serve as a means to inhibit the function of FasR in healthy neurons that surround damaged nervous tissue, in hopes of preventing increased damage to the irreparable nerve tissue.
In the nervous system, when FasL binds to FasR, the DISC begins the pathway within the cell to lead to its death. To prevent this, perform the SELEX method to select an RNA aptamer with a high binding affinity for FasR. This aptamer would serve as a means to inhibit the function of FasR in healthy neurons that surround damaged nervous tissue, in hopes of preventing increased damage to the irreparable nerve tissue.
Figure 1. By inhibiting the function of FasR in healthy
neurons surrounding trauma, loss of function can be minimized.
FasR/CD95 can be purchased from BD Pharmingen (Catalog#554256)
at the price of $255 for 500 micrograms. (http://www.bdbiosciences.com/ptProduct.jsp?prodId=10379&catyId=745875)
1. Kim, J.W., Choi, E., O Joe, C. 2000 “Activation
of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment
of RIP” Oncogene (19). 4491-4499
2. Beattie, M.S. 2004 “Inflammation
and apoptosis: linked therapeutic targets in spinal cord injury” Trends in
Molecular Medicine (12). 580-583
3. Groene, H-J., Herr, I., Krammer,
P.H., Martin-Villalba, A. 2006 “Control of neuronal brancing by the death
receptor CD95 (Fas/Apo-1)” Cell Death and Differentiation (13). 31-40
4. Shohami, E., Trentz, O., Kossman, T., Morganti-Kossman,
M.C. 2007 “Immunohistochemical characterization of Fas (CD95) and Fas Ligand (FasL/CD95L)
expression in injured brain: Relationship with neuronal cell death and
inflammatory mediators” Histol Histopathol (22) 235-250
2 comments:
Couldn't stopping cells from going through apoptosis lead to bigger problems such as cancer? Since the cells will be a little damaged from the physical drama to begin with? Just a thought.
Dear Owais,
Here are a few suggestions:
1. Can't wait to read your response to Ankita's comments ... immunity to death receptor, which you mentioned during our meeting
2. Per our meeting, I understand that you'd like to switch to angiotensinII ... please rewrite the abstract & schedule another meeting w/ me.
3. I like how you organized your abstract. You introduced a problem and then narrowed in on a keyplayer of the disease/malady. Next time, please offer an aptamer sol'n as part of the bulk of the abstract.
4. specific aim #1 - identify aptamer
5. specific aim #2 - develop aptamer diagnostic/therapeutic, or whatever your downstream application is.
6. Budget - please include molecular weight & cost per a round
Good abstract! I look forward to reading your angiotensin abstract.
Gwen
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