The聽study was sponsored by the聽National Institutes of Health鈥檚 National Institute on Aging聽and聽was led by 麻豆原创 Nanoscience Technology Center聽Professor聽James Hickman聽and聽Research聽Professor聽Xiufang 鈥淣adine鈥� Guo. In collaboration with聽researchers at聽healthcare tech company Hesperos, the team used聽lab-grown,聽human-cell systems designed to model how the body functions聽to聽examined聽how genetic mutations associated with聽familial聽Alzheimer鈥檚聽affects聽movement.聽Today, the聽study was published in聽Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

鈥淢otor deficits may be an earlier indication聽[of Alzheimer鈥檚],鈥� she聽says. 鈥淚f we can detect those changes and intervene earlier, that could help delay the onset of central nervous system symptoms.鈥�

How聽Movement and Alzheimer鈥檚 Are Connected

Familial Alzheimer鈥檚 is聽a聽rare聽form of the disease that聽is聽hereditary and appears聽earlier聽(from聽40 to 65 years of age)聽in people affected than those聽with the typical聽condition.

While聽Alzheimer鈥檚 disease is widely聽associated with聽memory loss and dementia,聽clinicians have long聽observed聽that some patients show changes in balance, gait聽(manner of walking)聽or movement years before cognitive symptoms appear. These聽early motor changes聽raise聽questions about whether聽parts of the disease begin聽outside the brain.

Through a tech-powered approach, the聽team found that the diseased motor neurons聽鈥斅爀ven without involvement from the brain聽鈥斅燿isrupted聽the neuromuscular junction, which is聽central to daily movement.

鈥淭his is the first time it鈥檚 been demonstrated that deficits in the peripheral nervous system can arise directly from these mutations,鈥� Hickman聽says. 鈥淚t means drugs that target the brain may not fix problems in the rest of the body.鈥�

Maintaining聽motor function may also聽support overall聽brain聽health,聽as聽physical activity is known to聽play a role in cognitive well-being, Guo notes.

How Researchers Build Human Disease Models in the Lab

To explore how these mutations affect movement, the researchers turned to a聽cutting-edge聽approach called 鈥渉uman-on-a-chip鈥� technology, which is manufactured聽through Hesperos, a company co-founded by Hickman.聽These miniature lab systems recreate the way human cells interact and function in the body, allowing scientists to study disease in a more realistic way than traditional lab or animal models.

The team built a neuromuscular junction-on-a-chip 鈥� a small system that mimics the connection between motor neurons and muscle cells.聽What makes聽this system powerful is聽what鈥檚聽left out: the brain and spinal cord. By isolating motor neurons and muscle cells, the researchers could聽determine聽whether movement problems could arise without the central nervous system being involved.

To test this, the researchers聽paired聽healthy聽muscle cells聽with聽motor neurons聽that were聽created from stem cells聽and聽carried聽familial Alzheimer鈥檚 disease聽mutations.聽The聽findings suggest that Alzheimer鈥檚-related movement issues may begin in the network of nerves outside the brain and spinal cord rather than being caused solely by brain degeneration.

Why the聽Nerve-to-Muscle Connection Matters

The neuromuscular junction is the point where a nerve cell signals a muscle to contract, making movement possible.聽If that connection is damaged, the body may lose strength,聽coordination聽or endurance.

In the study, the researchers measured several aspects of neuromuscular function, including how reliably nerve signals triggered muscle contraction and how long muscles could remain contracted before fatiguing. These measurements mirror the kinds of tests doctors use to evaluate movement disorders.

鈥淵ou can鈥檛 move unless the motor circuit works,鈥� Hickman聽says. 鈥淲hen a doctor taps your knee to check your reflex, they鈥檙e testing that exact connection.鈥�

The Future of聽鈥楬uman-on-a-Chip鈥櫬燭echnology

The researchers believe their approach will become increasingly important as drug developers look for more聽accurate聽ways to study human disease.

Because the models use human cells and measure real biological聽function, they can reveal effects that may not appear in animal studies.

For Hickman, the work reflects聽30 years of research to聽better understand disease and help people.

鈥淭hese systems let us study disease in a way that鈥檚 closer to what actually happens in the human body, and that鈥檚 what we need to develop better treatments,鈥澛爃e says.

Research reported in this article was supported by the National Institutes of Health鈥檚 National Institute on Aging under award number R01AG077651 and R44AG071386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Many of the grants, worth $7.2 million total, address challenges of national and global scale. Some smaller grants support promising new technology or potential discoveries that could lead to new treatments, such as a potential malaria-fighting drug made from marine microbes.

Here are some of the funded projects:

Tuberculosis ($429,000)

Typically, getting a diagnosis of tuberculosis takes time. A culture must be taken and usually sent to a lab for confirmation, and that means lots of time without treatment. The scenario is worse in remote regions of the world, where test results could take several weeks or months.

The goal is to enhance efforts to control the spread of tuberculosis. TB is a global health crisis which kills 2 million people each year because of a lack of an effective vaccine, emerging drug resistance, limited treatment options, and inadequate diagnostic tools.

Dmitry Kolpashchikov in 麻豆原创鈥檚 chemistry department, Kyle Rohde at the Burnett School of Biomedical Sciences at the 麻豆原创 medical school and partners in Germany are using their grant to develop a novel diagnostic tool that is accurate and quick, giving a medical professional results within 30 minutes.

鈥淭he inability to reliably detect active TB cases and rapidly determine drug susceptibility profiles in many high-incidence settings severely compromises the treatment and control of this disease,鈥� Kolpashchikov said.

HIV-1 ($436,000 grant)

Alexander Cole, a professor in the Burnett School of Biomedical Sciences, leads a team that is developing a way to use inexpensive and widely available antibiotics called aminoglycosides to restore the production of a potent human protein called retrocyclin. This protein prevents HIV-1 infection.

Humans early on were able to produce retrocyclin, but a mutation in one of our genes suppresses its production. By using aminoglycosides, the team has been able to boost the ability of the gene to begin producing the protein again.聽 The $436,000 grant will help the team continue its study.

鈥淏eing able to naturally bolster human鈥檚 ability to prevent HIV transmission could be extremely beneficial in limiting the global spread of HIV,鈥� Cole said.

Schizophrenia ($404,000 grant)

Associate professor Jeffrey Scott Bedwell is leading a group that is attempting to understand the underlying brain abnormalities and causes of schizophrenia. Many believe that like autism, schizophrenia may be an umbrella term that describes a range of disorders. Schizophrenia also has also been linked to early visual processing abnormalities, but very little is understood about that link.

鈥淭he proposed study will examine whether there are specific clusters of schizophrenia-related symptoms that relate to specific early visual processing abnormalities,鈥� Bedwell said in his research proposal. 鈥淭he results from this study will have strong potential to uncover new schizophrenia subtypes, thereby facilitating the search for more effective treatments and prevention programs.鈥�

Bedwell is part of the clinical psychology PhD program in the department of psychology and runs the Psychophysiology of Mental Illness Laboratory. His study will also look at the effect red light has on some patients with schizophrenia.

Spinal Reflex Arc ($388,000)

Professor James Hickman and his team at the NanoScience Technology Center are engineering a system model of one of the most fundamental motor circuits in the human body, the spinal reflex arc.

鈥淲e will use nanotechnology and microelectronics in combination with biomedical engineering techniques to build this hybrid biological/non-biological system,鈥� Hickman said in his proposal. 鈥淧otential benefits include learning enough to prevent, diagnose and treat developmental abnormalities in the spinal cord, rehabilitation of chronic neurological muscle disorders and new strategies for prosthetic and orthotic design and evaluation.鈥�

This technology has the potential to streamline the drug development process, accelerating the transition rate of compounds from laboratory to clinical environments.

鈥淲e hope that in time this work will help to develop advanced treatments for people suffering from severe peripheral neuropathies such as Lou Gehrig鈥檚 Disease and Myasthenia Gravis, and will have far reaching implications for the effective study of many human diseases in vitro,鈥� he added.

Rural Health Clinics and Healthcare ($378,000)

Judith Ortiz, a research associate professor at the College of Health and Public Affairs, leads a group that is examining health care delivered by Rural Health Clinics (RHCs) to older adults in the Southeastern U.S.

The team is analyzing several factors, including the participation of RHCs in Accountable Care Organizations, which impact patient outcomes and cost efficiency of RHCs.聽 The eight study states (Mississippi, Alabama, Florida, Georgia, South Carolina , North Carolina, Tennessee, and Kentucky) have many vulnerable populations 鈥� all have a higher percentage of persons in poverty, seven of them have a higher percentage of rural populations, and more than half of them have a higher percentage of persons aged 65 and over.

The study aims to provide information to assist policy leaders in making decisions that will strengthen the health care safety net in rural America.

鈥淚 am passionate about the benefits of primary health care and its emphasis on prevention of illness,鈥� Ortiz said. 鈥淚 am motivated to contribute to the improvement of health care delivery systems in rural areas where there is a growing need for improving health conditions and health care resources.鈥�

The research, scheduled to be released today, is featured in the inaugural issue of Technology, a 鈥渉igh-impact-striving鈥� trade journal designed specifically for the greater community of applied researchers, scientists and engineers worldwide. According to its website, Technology will feature the development of cutting-edge new technologies in a broad array of emerging fields of science and engineering.

According to James J. Hickman, Ph.D., professor of chemistry, biomolecular science and electrical engineering at the 麻豆原创, and the senior author of the work, this breakthrough could help speed up the long, arduous pharmaceutical development process.

鈥淭his technology, while exciting in itself, is part of a larger goal aimed to better mimic conditions in the body,鈥� Hickman said. 鈥淭he pharmaceutical industry is in desperate need of highly predictive pre-clinical screening systems to streamline the drug development process and shorten current validation protocols, which can take a decade to implement.鈥�

The work builds upon other notable discoveries and breakthroughs by Hickman-led research teams.聽 Earlier in the year, his team developed a method which uses non-embryonic stem cells to explore treatment options for spinal cord injuries and diseases such as multiple sclerosis.聽 In 2011, Hickman鈥檚 team developed a process which uses stem cells to grow neuromuscular junctions (key connectors used by the brain to control muscles) between human muscle cells and human spinal cord cells. Recently, development of the first derivation of sensory neurons was published in Biomaterials and featured in Neural Cell News 7.11, March 20, 2013.

Additional co-authors of the Technology paper include Alec Smith, PhD, Chris Long, PhD, and Kristen Pirozzi, BS. This work was supported by National Institutes of Health grants R01NS050452 and R01EB009429.

鈥淭his is the first time this has been done with non-embryonic stem cells,鈥� says James Hickman, a 麻豆原创 bioengineer and leader of the research group, whose accomplishment is described in the Jan. 18 issue of the journal ACS Chemical Neuroscience.

鈥淲e鈥檙e very excited about where this could lead because it overcomes many of the obstacles present with embryonic stem cells.鈥�

Stem cells from umbilical cords do not pose an ethical dilemma because the cells come from a source that would otherwise be discarded. Another major benefit is that umbilical cells generally have not been found to cause immune reactions, which would simplify their potential use in medical treatments.

The pharmaceutical company Geron, based in Menlo Park, Calif., developed a treatment for spinal cord repair based on embryonic stem cells, but it took the company 18 months to get approval from the FDA for human trials due in large part to the ethical and public concerns tied to human embryonic stem cell research.聽 This and other problems recently led to the company shutting down its embryonic stem cell division, highlighting the need for other alternatives.

Sensitive Cells

The main challenge in working with stem cells is figuring out the chemical or other triggers that will convince them to convert into a desired cell type. When the new paper鈥檚 lead author, Hedvika Davis, a postdoctoral researcher in Hickman鈥檚 lab, set out to transform umbilical stem cells into oligodendrocytes–critical structural cells that insulate nerves in the brain and spinal cord–she looked for clues from past research.

Davis learned that other research groups had found components on oligodendrocytes that bind with the hormone norephinephrine, suggesting the cells normally interact with this chemical and that it might be one of the factors that stimulates their production. So, she decided this would be a good starting point.

In early tests, she found that norepinephrine, along with other stem cell growth promoters, caused the umbilical stem cells to convert, or differentiate, into oligodendrocytes. However, that conversion only went so far. The cells grew but then stopped short of reaching a level similar to what鈥檚 found in the human nervous system.

Davis decided that, in addition to chemistry, the physical environment might be critical.

To more closely approximate the physical restrictions cells face in the body, Davis set up a more confined, three-dimensional environment, growing cells on top of a microscope slide, but with a glass slide above them. Only after making this change, and while still providing the norephinphrine and other chemicals, would the cells fully mature into oligodendrocytes.

鈥淲e realized that the stem cells are very sensitive to environmental conditions,鈥� Davis said.

Medical Potential

This growth of oligodendrocytes, while crucial, is only a first step to potential medical treatments. There are two main options the group hopes to pursue through further research. The first is that the cells could be injected into the body at the point of a spinal cord injury to promote repair.

Another intriguing possibility for the Hickman team鈥檚 work relates to multiple sclerosis and similar conditions. 鈥淢ultiple sclerosis is one of the holy grails for this kind of research,鈥� said Hickman, whose group is collaborating with Stephen Lambert at 麻豆原创鈥檚 medical school, another of the paper鈥檚 authors.

Oligodendrocytes produce myelin, which insulates nerve cells, making it possible for them to conduct the electrical signals that guide movement and other functions. Loss of myelin leads to multiple sclerosis and other related conditions such as diabetic neuropathy.

The injection of new, healthy oligodendrocytes might improve the condition of patients suffering from such diseases. The teams are also hoping to develop the techniques needed to grow oligodendrocytes in the lab to use as a model system both for better understanding the loss and restoration of myelin and for testing potential new treatments.

鈥淲e want to do both,鈥� Hickman said. 鈥淲e want to use a model system to understand what鈥檚 going on and also to look for possible therapies to repair some of the damage, and we think there is great potential in both directions.鈥�

Besides Hickman and Davis, the other authors on the paper were Xiufang Guo, Stephen Lambert, and Maria Stancescu, all from the 麻豆原创.

鈥淭hese types of systems have to be developed if you ever want to get to a human-on-a-chip that recreates human function,鈥� said James Hickman, a 麻豆原创 bioengineer who led the breakthrough research. 鈥淚t鈥檚 taken many trials over a number of years to get this to occur using human derived stem cells.鈥�

Hickman鈥檚 work, funded through the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health, is described in the December issue of .

Hickman is excited about the future of his research because several federal agencies recently launched an ambitious plan to jump-start research in 鈥渉uman-on-a-chip鈥� models by making available at least $140 million in grant funding.

The National Institutes of Health (NIH), the Defense Advanced Research Projects Agency (DARPA), and the Federal Drug Administration (FDA) are leading the research push.

The goal of the call for action is to produce systems that include various miniature organs connected in realistic ways to simulate human body function. This would make it possible, for instance, to test drugs on human cells well before they could safely and ethically be tested on living humans. The technique could potentially be more effective than testing in mice and other animals currently used to screen promising drug candidates and to develop other medical treatments.

Such conventional animal testing is not only slow and expensive, but often leads to failures that might be overcome with better testing options. The limitations of conventional testing options have dramatically slowed the emergence of new drugs, Hickman said.

The successful 麻豆原创 technique began with a collaborator, Brown University Professor Emeritus Herman Vandenburgh, who collected muscle stem cells via biopsy from adult volunteers. Stem cells are cells that can, under the right conditions, grow into specific forms. They can be found among normal cells in adults, as well as in developing fetuses.

Nadine Guo, a 麻豆原创 research professor, conducted a series of experiments and found that numerous conditions had to come together just right to make the muscle and spinal cord cells 鈥渉appy鈥� enough to join and form working junctions. This meant exploring different concentrations of cells and various timescales, among other parameters, before hitting on the right conditions.

鈥淩ight now we rely a lot on animal systems for medical research but this is a pure human system,鈥� Guo said. 鈥淭his work proved that, biologically, this is workable.鈥�

Besides being a key requirement for any complete human-on-a-chip model, such nerve-muscle junctions might themselves prove important research tools. These junctions play key roles in Amyotrophic lateral sclerosis, commonly known as Lou Gehrig鈥檚 disease, in spinal cord injury, and in other debilitating or life threatening conditions. With further development, the team鈥檚 techniques could be used to test new drugs or other treatments for these conditions even before more expansive chip-based models are developed.

The grant represents a collaboration between Dr. Lambert, a myelin biologist and Dr. James Hickman a bioengineer in the 麻豆原创 Nanoscience Center, whose team showed for the first time last year that myelin could be produced in the lab environment without the use of any type of growth serum. That finding is significant because it allows researchers to more clearly study the causes of breaks in myelin and also the impact of proposed drug treatments.

The research will be carried out at the Burnett School of Biomedical Sciences building at the 麻豆原创 Health Sciences Campus at Lake Nona and in Dr. Hickman’s specialized lab in the Nanoscience Center at 麻豆原创. “The ability to reproduce the complex phenomenon of myelination under controlled conditions, and then induce demyelination under the same conditions, will allow us to have a greater understanding of what happens in these debilitating demyelinating disorders. Current therapeutics focus mainly on controlling the inflammatory nature of diseases such as MS to limit the development of neuronal damage. The long-term goal of this research is to try and come up with new mechanisms and therapeutics for reversing that damage and its terrible consequences,” said Dr. Lambert.

“The application of the high-tech tools developed in my lab at the Nanoscience Center to this complex problem of myelination and demyelination brings us that much closer to developing new therapeutics and at some stage a cure for diseases such as MS,” Dr. Hickman said.