Expanding the Range of Nature’s Catalysts for Industrial Applications PDF Print E-mail
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Tuesday, 04 February 2014 14:58

Expanding the Range of Nature’s Catalysts for Industrial Applications

Wed, 2014-01-29 15:30
NSF Awards $1.7 Million Grant to Rensselaer Researcher George Makhatadze
January 29, 2014

To make paper, manufacturers must break down cellulose (chunks of wood pulp), a process that currently requires large amounts of energy and toxic chemicals like chlorine. Nature performs the same task using enzymes, non-toxic biodegradable proteins that accelerate chemical reactions using far less energy. The catch is that the enzymes required for the job, in this case xylanases, don’t hold up to the high temperatures of the manufacturing process. This is only one of many examples of how the limitations of enzymes hamper the development of elegant solutions in the manufacture of everything from medicine to detergents.

“So the question is: can we improve on nature?” said George Makhatadze, a chaired professor in the Biocomputation and Bioinformatics research constellation, professor of biological sciences, and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute. “Can we take an existing protein and, using computation, redesign it to withstand higher temperatures?”

Makhatadze designs “custom proteins,” and is an expert in the critical interaction between electrical charges on the surface of proteins. Within the School of Science, Makhatadze’s research is part of an interdisciplinary theme of modeling, analysis, and simulation. His research is also part of a CBIS research focus on protein engineering. In a 2009 edition of the Proceedings of the National Academy of Science (PNAS), his lab presented a computer model that enhances protein thermostability, while retaining full enzymatic activity. Now, with the support of a five-year, $1.7 million National Science Foundation grant, Makhatadze will investigate the speed of protein folding.

Enzymes are composed of long strings of amino acids. As the string is assembled, electrostatic forces along its length interact, causing it to twist and turn, and ultimately fold into a stable three-dimensional shape. The enzyme functions properly only when folded into this shape, and typically retains its structure within a narrow range of conditions. If subjected to temperature, pH, or pressure outside these tolerances, the enzyme begins to denature, losing its shape and functionality.

Makhatadze seeks to boost the high-temperature tolerances for a given enzyme by adjusting the electrostatic interactions on the protein surface. In research culminating with the 2009 PNAS paper, Makhatadze developed a computer program allowing researchers to expand the temperature range at which a given enzyme would remain functional by altering the electrical charges on the protein surface. 

“Many forces – the packing of the core, hydrophobic interactions, hydrogen bonding, salt bridges, disulfide bridges – are important for protein stability, and 40 years of research has gone into establishing the rules that govern this process,” said Makhatadze. “Our contribution has been on the particular role of the interactions between the charges on the protein surface, and a recognition that they can be manipulated to modulate protein stability.”

In the context of industrial processes like paper manufacturing, the expanded functional range could make an enzymatic approach more attractive and economically feasible. The next step, said Makhatadze, and the focus of the NSF grant, is to understand the speed at which proteins fold and unfold, in order to slow their deterioration, and further expand their functional range.

“We’ve learned to make changes in the stability of the protein. But every protein has a limit; there’s nothing you can do to make a protein stable at 500 degrees, for example,” said Makhatadze. “So can we somehow make it unfold more slowly by modulating the charge-charge interactions? If you can extend that process, it will function at a high temperature for a longer period of time, and that’s beneficial.”

Within CBIS, the $1.7 million commitment from the NSF is one of several new multimillion-dollar research awards, raising research expenditures in 2014 despite a challenging funding environment.

 
Rensselaer In The News: 7 Cool New Findings About the Brain PDF Print E-mail
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Tuesday, 14 January 2014 11:02

January 9, 2014 | via: Huffington Post - Peter Tessier of Rensselaer Polytechnic Institute is working to engineer antibodies that have precise properties. By placing DNA sequences from a target protein within antibodies, Tessier may design the antibodies to bind to select proteins, such as proteins linked with Alzheimer's called beta-amyloid plaques. Further research may lead to the development of antibodies that recognize and remove toxic particles before they do harm.

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Last Updated on Tuesday, 14 January 2014 11:14
 
Congenital Diaphragmatic Hernia Traced from Genetic Roots to Physical Defect PDF Print E-mail
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Tuesday, 14 January 2014 10:27

Rensselaer Researchers Contribute to Discovery of Gene Associated With Deadly Birth Defect

                                                             

Troy, N.Y. – A team including researchers from Rensselaer Polytechnic Institute have discovered that a specific gene may play a major role in the development of a life-threatening birth defect called congenital diaphragmatic hernia, or CDH, which affects approximately one out of every 3,000 live births.

 

The hallmark of CDH is a rupture of the diaphragm that allows organs found in the lower abdomen, such as the liver, spleen, and intestines, to push their way into the chest cavity. The invading organs crowd the limited space and can lead to abnormal lung and heart development or poor heart and lung function, which, depending on the severity of the condition, can cause disability or death.

 

In a paper published recently in the Journal of Clinical Investigation, lead authors at the University of Georgia, along with colleagues from the Rensselaer and the University of California at San Diego, demonstrated for the first time that the gene NDST1 plays a significant role in the proper development of the diaphragm, and that abnormal expression of the gene could lead to CDH.

 

“We now have a really good picture of this abnormality in mice, and we suspect it is very similar in humans,” said Fuming Zhang, a research professor in the laboratory of Robert J. Linhardt, the Ann and John H. Broadbent Jr ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering, and a member of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer. “What this gives us is a total view, from the genetic level, to the molecular level, to the cellular or tissue level, to something that a physician would see — a hernia in a newborn.”

 

The discovery began with the observation that mice bred without the NDST1 gene, which produces the eponymous NDST1 enzyme, are more likely to develop CDH than ordinary mice. The enzyme NDST1 is one of four isoforms — a group of molecules that are chemically similar, but show subtle functional differences. In mice lacking the NDST1 gene, and therefore the NDST1 enzyme, nature substitutes with an NDST1 isoform (NDST2, NDST3, and NDST4), but the results — like substitutions in cooking — are noticeable.

 

In the absence of NDST1, blood vessels supplying the developing diaphragm muscles formed inconsistently, leading to weak points in the muscle tissues that make them prone to hernia. Researchers knew that the NDST1 enzyme is involved in the synthesis of heparan sulfate, so the group turned to the Linhardt’s research team at Rensselaer – experts in heparan sulfate and glycosaminoglycan analysis – to pinpoint the biochemical basis for the abnormality.

 

“There are two molecules in the interaction that leads to proper blood vessel formation in the diaphragm — NDST1 biosynthesized heparan sulfate and the protein SLIT3,” said Zhang. “In order for those interactions to be successful, and for blood vessels to form properly, everything must be accomplished within a specific time frame and having a specific structure. We were able to investigate the interactions between the two.”

 

Zhang used surface plasmon resonance spectroscopy to measure aspects of the interaction such as the rate at which the two molecules bound together, the strength of their interaction, and the molecular structure of heparan sulfate required for a successful interaction. The results of his measurements explain the inconsistent blood vessel growth and weak muscle tissue observed in the mice.

 

“The binding strength, the binding rate, and the length of the heparan sulfate required for binding to the SLIT3 protein are inadequate for the job in this defect,” said Zhang. “We were able to understand why, at a molecular level, this failure in development takes place.”

 

Linhardt said the findings allow researchers to think about “routes for intervention at all levels.” Gene therapy might supply the correct gene, drugs might deliver a substitute molecule, tissue engineering might enable the tissue to repair itself, or a surgeon might repair the damage after a hernia has occurred.

 

“We understand that the muscle is damaged because blood flow is damaged because the vascular system feeding the blood flow isn’t forming properly,” said Linhardt. “Because we now understand what is wrong, it allows us to think about the opportunity for therapy at all levels.”

 

Contact

Mary Martialay

Rensselaer Polytechnic Institute

(518) 276-2146

(518) 951-5650 (mobile) 

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Last Updated on Tuesday, 14 January 2014 10:51
 
RPI - ISMMS Seed Funding PDF Print E-mail
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Friday, 10 January 2014 10:29

We are pleased to announce the awardees of the inaugural Rensselaer-­‐Icahn School of Medicine at Mount Sinai seed funding program to advance collaborative science between the two institutions. These projects were selected from among 29 excellent applications. The remarkably enthusiastic response reflects a strong mutual interest in aligning the strengths of each institution to advance discovery and innovation in biomedical sciences and engineering. These projects underscore the value of cross-­‐disciplinary teams in translating our science into new technologies.

We congratulate the awardees and all the applicants for embracing this opportunity, and look forward to learning of the new advances the projects generate.

Awardees (Rensselaer PI listed first):

1. Effects of Retrotransposons on genome stability and consequence for the biology of aging and cancer (P. Maxwell & M. O’Connor)
2. In situ generation of tissue-­‐engineered vascular conduits using PDGFRα+ vascular progenitor cells (M. Hahn & J. Kovacic)
3. Inhibiting hepatitis C virus with high affinity single-­‐domain antibodies (P. Tessier & M. Evans)
4. Proteoglycan metabolism and painful intervertebral disc degeneration (R. Linhardt & J. Iatridis)
5. Toward a Universal Influenza Virus Vaccine: Development of Nanoscale Constructs that Elicit Broadly Neutralizing Antibodies (R. Kane & P. Palese)
6. Continuous Monitoring of Compartmental Pressures for Objective Diagnosis of Compartment Syndrome (E. Ledet, K. Connor & D. Forsh, J. Gladstone)
7. Inducing Targeted Mutations in Cells in the Brain In Vivo (can Dopamine Transporter be modified to resist drug abuse) (S. Kotha & E. Nestler)
8. ReDrugS: Repurposing Drugs using Semantics (D. McGuinness & J. Dudley)

The Rensselaer-­‐Icahn School of Medicine at Mount Sinai Joint Steering Committee
Rensselaer: Jonathan Dordick, Wolf van Maltzahn, Deepak Vashishth
Mount Sinai: Geoffrey Smith, John Morrison, Scott Friedman

 

Last Updated on Friday, 10 January 2014 10:33
 
Researchers at Rensselaer Polytechnic Institute Uncover Mechanism of Genetic Mutations Known To Cause Familial Alzheimer’s Disease PDF Print E-mail
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Friday, 10 January 2014 08:57
Researchers at Rensselaer Polytechnic Institute Uncover Mechanism of Genetic Mutations Known To Cause Familial Alzheimer’s Disease
Thu, 2014-01-09 15:37 -- katzme

New Study Pinpoints Structural Effects of V44M and V44A Mutations

January 9, 2014

New research, led by Rensselaer Polytechnic Institute researcher Chunyu Wang, has solved one mystery in the development of Familial Alzheimer’s Disease (FAD), a genetic variant of the disease that affects a small fraction of the Alzheimer’s population. In a paper published January 6 in the journal Nature Communications, Wang and his team follow the trail of two genetic mutations – V44M and V44A – known to cause FAD, and show how the mutations lead to biochemical changes long linked to the disease.

The hallmark of FAD is the accumulation of the Amyloid Beta 42 peptide (a short chain of amino acids) in unusually high concentrations within the brain. In a healthy brain, Amyloid Beta-42 (Aβ42) and a similar peptide, Amyloid Beta-40 (Aβ40), are found in a ratio of about 1 to 9. In a brain affected by FAD, this ratio is much higher. The two peptides are nearly identical:  Aβ40 is a chain of 40 amino acids in length; Aβ42 is 42 amino acids in length. However, Aβ42 is much more toxic to neurons and plays a critical role in memory failure.

“The mutations that cause FAD lead to an increased ratio of Aβ42 over Aβ40,” said Wang, an associate professor of biological sciences within the School of Science, director of the biochemistry and biophysics graduate program, and member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies, who co-wrote the paper with Wen Chan, a graduate student at Rensselaer. “That’s the biochemistry, and that has been observed by many people. But the question we asked is: how? How do the mutations lead to this increased ratio?”

There are hundreds of known genetic mutations linked to FAD, but they are all related to the processing of a large protein, the amyloid precursor protein (APP), which starts its life partially embedded in the cell membrane of brain cells, and is later cut into several pieces, one of which becomes either Aβ42 or Aβ40.

In a multi-step process, enzymes make several cuts to APP, and the location of the cuts dictates whether a resulting snippet of APP becomes Aβ42 or Aβ40. If an enzyme, γ-secretase, makes an initial cut at an amino acid within APP called Threonine 48 (T48), the remaining cuts result in Aβ42, whereas if the first cut is made at amino acid Leucine 49, the process will result in Aβ40.

Wang’s team used solution nuclear magnetic resonance spectroscopy to study the three-dimensional structure and dynamics of the transmembrane portion of APP affected by the two genetic mutations, and they discovered that the mutations cause a critical change to the T48 amino acid. That change makes it more likely that γ-secretase will prefer a cut at T48, leading to production of Aβ42, and increased concentrations of Aβ42 found in the brains of patients with FAD.

“The basic idea is that – in the mutated versions – this site, T48, becomes more open, more accessible to γ-secretase,” said Wang. “What we found is that the FAD mutation basically opens up the T-48 site, which makes it more likely for γ-secretase to produce Aβ42 peptide.”

The paper, titled “Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of Ɛ-cleavage site,” is available online at: http://go.nature.com/EIkz6C.

Last Updated on Monday, 13 January 2014 08:35
 
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