好色先生TV

For years, scientists have suspected that microscopic traces left by a lifetime of encounters with viruses, bacteria and fungi may drive age related decline. Despite growing evidence that these encounters spark inflammation, disrupt cellular machinery, and potentially accelerate diseases like Alzheimer鈥檚, scientists have lacked the tools to observe these molecular interactions directly.

A new project led by 好色先生TV aims to change that.

Yongxin (Leon) Zhao, the Eberly Family Career Development Associate Professor of Biological Sciences, and collaborators at MIT and the University of Pittsburgh, have received a $500,000 grant from the Richard King Mellon Foundation to build next generation imaging tools capable of capturing, in nanoscale detail, how microorganisms interact with the cells and molecules of the aging brain.

鈥淲e really want to see how these things might be driving aging,鈥� Zhao said. 鈥淏y creating the ability to see precisely how and where microbes inflict damage at a molecular level, this work will unlock entirely new avenues for developing diagnostics and therapies for age-related diseases 鈥� shifting the paradigm from managing symptoms to targeting root causes of aging.鈥�

For decades, the brain was considered sterile, shielded from microbes by the blood brain barrier. But recent studies suggest that the brain may host up to 100,000 different microbial species. And scientists have linked infections like gum disease and cold sores to increased dementia risk. Yet the physical evidence 鈥� the actual nanoscale interactions inside brain tissue 鈥� has remained elusive.

鈥淭he critical interactions between a pathogen and a host cell occur at the nanoscale, deep within the complex, three-dimensional architecture of our tissues, amidst a heterogeneous molecular environment,鈥� Zhao said. 鈥淲e are currently 鈥榝lying blind鈥� at this scale.鈥�

Available techniques, from conventional microscopy to electron microscopy, lack the resolution or the ability to handle the complexity of mapping dozens of different proteins simultaneously. Those are the problems Zhao鈥檚 team intend to solve.

Zhao is collaborating with , the Y. Eva Tan Professor in Neurotechnology at MIT, who develops novel tools to analyze, repair, and simulate the brain, and , an assistant professor of ophthalmology at the University of Pittsburgh and an assistant professor at the Hebrew University of Jerusalem, an expert in developing novel molecular and optical tools to study and reverse brain disease.

鈥淭he project鈥檚 greatest asset is its interdisciplinary team of principal investigators and their labs,鈥� said Boyden, who mentored Zhao and Shemesh as postdoctoral researchers. 鈥淏y joining together, the three of us could really advance our understanding of the brain鈥檚 patho-microbiome.鈥�

鈥淚 really like working with Ed and Yongxin, who are driving the technology development. From the user side, I get to benefit directly from what they create,鈥� said Shemesh, whose lab is investigating the role microbes play in Alzheimer鈥檚 disease, Parkinson鈥檚 disease, chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). 鈥淢icroorganisms are extremely small and often elusive. I鈥檓 fortunate to work closely with them as the tools continue to develop.鈥�

is a leader in the field of expansion microscopy, a technique that enables super-resolution imaging of biological samples by physically enlarging the tissue using a swellable hydrogel. This spreads molecules apart so they can be imaged with nanoscale clarity using standard microscopes. For the current project, Zhao is designing an enhanced version of his expansion microscopy platform, dubbed Magnify, that will be capable of imaging dozens of microbial and host proteins simultaneously in thick, aged brain tissue.

Boyden is adapting his iterative expansion microscopy technique, which expands specimens over and over again, for the specialized problem of studying the microbe-brain interface. By identifying proteins stained with small molecule chemical stains, such microscopy methods eliminate the need for antibodies, which are typically used to bind to a target protein and light-up once bound. By eliminating the need for antibodies, researchers may detect unexpected proteins at pathogen host interfaces.

In the Shemesh lab, the team will apply their new tools in a mouse model infected with microorganisms that have been linked to Alzheimer鈥檚 disease. The goal is to produce the first nanoscale 3D maps of each microbe鈥檚 position relative to hallmark Alzheimer鈥檚 features, such as amyloid 尾 plaques and tau tangles, and to identify the proteins directly at the microbe host interface.

鈥淏y creating the ability to see what is currently unseen, our technology will not only answer fundamental questions about the mechanisms of aging but will also unlock entirely new avenues for developing targeted therapies for a host of age-related diseases,鈥� Zhao said.

The tools developed in this project will be made widely available to the research community, enabling scientists around the world to investigate microbial triggers in neurodegeneration, inflammation, metabolic disorders and other age related conditions.

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