Molecular Systems Pharmaceutics

Prof. Yasuo Uchida

【Research Keyword】
 Drug discovery and treatment of various central nervous system disorders, Systems biology, Quantitative proteomics, Pharmacokinetics, Pharmaceutics, Blood-brain barrier, Blood-arachnoid barrier, Blood cerebrospinal fluid barrier, Blood-spinal cord barrier, human pathological brain tissues, Transporters, Receptors, Mass spectrometry, Drug delivery

【Recent highlights】
 Our research aims to unravel the mechanisms of the central nervous system barriers using state-of-the-art omics technology and make a breakthrough in central nervous system disease drug discovery.
 In 2022, 15 publications were published, of which eight were by laboratory students as first authors. Based on daily research activities and seminar presentations (in Japanese and English) in the laboratory, our education places great emphasis on students presenting their own research in papers and other publications as well as conference presentations.
 In 2023, Prof Uchida has been already invited for a variety of conference lectures (17 times from March 2023 to March 2024).
 The most common employment opportunities for laboratory students are researchers in pharmaceutical companies, but there are also clinical development positions, CROs, pharmacists and civil servants, etc.

Profiles of Faculty and Research Scholars

【Education】
 Lectures and practical training provide general education in the fundamentals of pharmacokinetics and pharmaceutics. Once assigned to a laboratory, students are educated to acquire a broad cross-disciplinary perspective based on these disciplines, incorporating a variety of disciplines and techniques such as biochemistry, molecular biology, pharmacology, analytical chemistry, bioinformatics and proteomics.
 Research is an activity in which everyone has the potential to succeed and excel, regardless of their lecture grades during their undergraduate years. The key to this is whether you enjoy it. It takes a certain amount of effort and time to be able to enjoy any art or sport as an athlete. In research, there is the pleasure of being the first person in the world to discover something that no one else in the world has seen, and the pleasure of being able to experimentally prove your ideas. We will do our best to support you so that you can enjoy this pleasure.
 We also encourage you to take up the challenge of a Ph.D. Your twenties are the time in your life when you can test and develop yourself the most. It is said that the talks of people who have been immersed in one thing for five years or more is interesting. A Ph.D. is an invaluable life confidence, as the problem-solving skills developed through a variety of experiences and trial-and-error during Ph.D. course can be applied to any field and in a wide variety of occupations.

【Research】
 In addition to the blood-brain barrier (BBB), three types of barrier tissue exist in the central nervous system (CNS): the blood-cerebrospinal fluid barrier (BCSFB), the blood-arachnoid barrier (BAB) and the blood-spinal cord barrier (BSCB), which separate the peripheral (blood) and CNS tissues. Collectively, these are called the “CNS barriers”.

 

Challenges in the development of new drugs for the treatment of CNS diseases
 (1) As the general concept is that the target molecules of drugs exist in the CNS beyond the CNS barrier, (2) drugs need to pass through the CNS barrier to reach the CNS, but more than 99% of drugs are prevented from entering the CNS by efflux pumps such as P-glycoprotein (P-gp). (3) Proteins, genes, nanoparticles and other macromolecules cannot pass through the CNS barrier at all. In order to solve these important problems, we are working daily to realize the following four concepts, with the aim of creating a new discipline, 'Barrier Control Science'.

 

Concept 1.
 Drug discovery that does not require the passage of the CNS barrier. Brain migration issues will be solved by targeting the cells of the CNS barrier itself as the target of drugs. As the CNS barrier influences the environment in the brain, for better or worse, we are going to establish an unprecedented new drug discovery strategy in which diseases in the CNS are caused by abnormalities in the barrier, and by treating these abnormalities, CNS diseases are treated.
 Currently, we are mainly working on this concept 1.

Concept 2.
 Establish a technology to selectively deliver RNA-loaded lipid nanoparticles into CNS cells using a membrane protein that is not found in other organs and is highly expressed specifically in the CNS barriers. This will save as many as 80% of candidate compounds that have dropped out in drug development, by delivering P-gp siRNA to knock down P-gp only in the CNS barrier and improving the brain penetration of those compounds without side effects. In addition, we are going to rapidly deliver the lipid nanoparticles to CNS tissues by using the appropriate receptor that can be internalized at high speed.

Concept 3.
 Create a mechanism for low-molecular medicines to be synthesized in barrier cells. In other words, the enormous amount of compounds that have been dropped out in the history of drug discovery because they cannot pass through the barrier in their original structure, although they have pharmacological effects, will be found to be of value. Specifically, by constructing a mechanism to deliver compounds to the barrier cells in a structure that can easily reach the barrier, cause chemical reactions in the barrier cells and convert them into active compounds with pharmacological effects, compounds that have never reached the central nervous system or had side effects in peripheral organs can be used as therapeutic agents for CNS disorders.

Concept 4.
 Just as the diagnosis of vascular age is used to check lifestyle-related diseases, we would like to predict the onset of future CNS disorders by diagnosing the 'Age' of the CNS barrier. Worldwide, the diagnosis of CNS diseases cannot be made by taking a sample of the brain and biopsying it, so diagnosis using blood biomarkers or by delivering imaging probes to the brain for testing is the mainstream method. However, abnormal substances in the brain do not easily penetrate the barrier and do not appear in the blood, and imaging probes are limited to those with good brain migration properties. In contrast, as the CNS barrier cells face the blood and their components easily flow out into the blood, the condition of the CNS barrier can be diagnosed by capturing abnormal molecular mechanisms in the barrier and targeting some of the components for blood diagnosis. In addition, because diagnostic probes can be introduced selectively into the CNS barrier by the mechanism described above, all kinds of diagnostic probes can be introduced and the environment of the CNS can be measured, regardless of whether the diagnostic probes themselves have good or bad brain migration properties. The condition of CNS barriers, that is, 'Age' reflects a predictor of CNS diseases, so this CNS barrier diagnosis can dramatically change the diagnostics of CNS diseases.


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