Stanford ChEM-H solicited proposals from small teams of clinicians and scientists or engineers who are interested in undertaking exploratory studies involving human subjects.
The mission of Stanford ChEM-H is to understand human biology at a molecular level, and to engineer molecules, materials and tools that will impact human health. A key limiting factor for testing molecular hypotheses or evaluating promising new tools in humans is the establishment of productive connections between molecular scientists/engineers with access to innovative tools and practicing clinicians with access to sick or healthy cohorts of human subjects. Together, these scholars can test bold hypotheses in humans, or validate the utility of a new tool in the diagnosis or management of a disease. Six proposals were selected from a competitive pool of applications for one year of funding beginning in March 2018.
"Protease Activity Detection in Human Eye Liquid Biopsies"
Laboratory Based Investigator: Polly Fordyce, Bioengineering
Clinical Based Investigator: Vinit Mahajan, Ophthalmology
Proteases underlie the pathogenesis of numerous blinding vitreoretinal diseases. Dr. Mahajan is an expert in vitreous proteomics, biochemistry, and ophthalmic surgery. His team is capable of collecting high-quality surgical specimens of the human vitreous humor for biochemical and proteomic analysis. Utilizing this platform, the Mahajan lab has identified over 200 proteases in the human vitreous. However, it is not possible to rapidly measure their activity in a high- throughput manner. Dr. Fordyce has recently developed novel high-throughput, microfluidic technologies that quantitatively measure protease activity. The experiments outlined in this proposal will combine their expertise to identify which proteases are functionally active during different eye diseases. At the completion of this study, key proteases active in eye disease will have been identified. These biomarkers may help diagnose diseases and establish specific therapeutic pathways for validation.
"Discovery of a Protective T Cell Receptor Molecular Signature for Human Cytomegalovirus Reactivation after Organ Transplantation"
Laboratory Based Investigators: Olivia Martinez, Surgery - Abdominal Transplantation; Mark Davis - Microbiology and Immunology
Clinical Based Investigator: Stephan Busque, Surgery - Abdominal Transplantation
Cytomegalovirus (CMV) is a common human viral pathogen that has infected the majority of adults worldwide but, in healthy individuals, CMV is usually controlled by the immune system without clinical consequences. Studies have shown that a type of white blood cell, termed T cells, are the main component of the immune system responsible for fighting CMV infection. On the other hand, in certain immunosuppressed or immunocompromised individuals, CMV infection can be quite serious. In solid organ transplant recipients CMV disease can lead to graft loss and death. This can arise as a result of initial infection or reactivation of a prior infection that had been silent. We are learning more about the T cells that are responsible for controlling CMV in transplant patients, however, we still don't know the exact fingerprint of the critical T cell population. In this study we determine the specific molecular pattern of T cells that controls CMV in transplant recipients. This would help us identify patients at higher risk of CMV disease and would improve management of solid organ transplant recipients to prevent graft loss and death.
"Functional Consequences of Novel Aldehyde Dehydrogenase Variants on Reducing Reactive Aldehyde Metabolism in Humans"
Laboratory Based Investigator: Daria Mochly-Rosen, Chemical and Systems Biology
Clinical Based Investigator: Eric Gross, Anesthesiology, Perioperative and Pain Medicine
Nearly 560 million people flush after drinking alcohol due to a genetic variant in aldehyde metabolism that causes a loss of enzymatic activity. Although this enzyme deficiency was considered benign, mounting clinical and epidemiological studies confirm increased risk for subjects with decreased enzymatic activity for a variety of common diseases, including osteoporosis, stroke and heart disease. Furthermore, use of alcohol or cigarettes for those who flush increases the risk for cancer by 100-fold. Therefore, identifying subjects with reduced aldehyde metabolism is of clinical importance. So far, only one such variant was described; the one found in East Asians. Mining large sets of genetic data coupled with biochemical studies, however, led us to identify other ethnic groups with likely high frequency of inactive or reduced activity of aldehyde detoxifying enzymes. Here we plan to develop an assay using human breath analysis to determine if indeed a loss of function variant(s) in aldehyde metabolism is common in non-East Asian ethnic groups. Identification of people who cannot efficiently break down aldehydes can lead to developing precise measures to provide medical care including advice on specific environmental exposures to avoid while also encouraging healthy lifestyle choices.
"Identifying Circulating Bacterial Small Molecules in Patients with Liver Disease"
Laboratory Based Investigator: Michael Fischbach, Bioengineering
Clinical Based Investigator: W. Ray Kim, Medicine - Gastroenterology & Hepatology
The purpose of this study is to learn more about the molecules produced by the human gut bacteria. The liver filters 95% of the blood from the gut, which includes nutrients from food and small molecules from human gut bacteria. Our study examines whether patients with liver disease have higher circulating concentrations of gut bacteria molecules and whether these molecules are associated with disease complications. Specifically, our study will examine patients who have liver disease and receive the TIPS procedure, a procedure that bypasses the liver and connects intestinal blood to the rest of the blood circulation in the body. By sampling blood before and after the TIPS procedure, we hope to learn more about molecules that are produced by the gut bacteria and are filtered (or not filtered) by the liver. Some of these molecules could be important for the development of complications of liver disease such as hepatic encephalopathy. Hepatic encephalopathy is a clinical condition that affects patients with liver disease and causes them to become confused and drowsy. If we are ultimately able to find molecules and bacteria that are associated with hepatic encephalopathy, we might be able to devise future treatment for this condition.
"Identification and Characterization of Immunomodulatory Epigenetic Changes Induced by IL-10 during Tr1 Cell Induction and Function"
Laboratory Based Investigator: Rosa Bacchetta, Pediatrics – Stem Cell Transplantation; Maria Grazia Roncarolo, Pediatrics – Stem Cell Transplantation
Clinical Based Investigator: Rajni Agarwal-Hashmi, Pediatrics – Stem Cell Transplantation
Medical complications after transplant of stem cells from a genetically different person (donor) can lead to morbidity and mortality. One of these complications is called graft-versus-host disease (GvHD) and is the major deterrent from patients receiving donor derived hematopoietic stem cell transplants (allo-HSCT). Developing strategies to mitigate GvHD will substantially improve outcomes for allo-HSCT recipients. We have developed a donor-derived cell product that confers anti-GvHD properties to allo-HSCT recipients. This product, T-allo10, is enriched for type 1 regulatory (Tr1) cells that induce tolerance. We are currently testing T- allo10 in a clinical trial in children with leukemia undergoing allo-HSCT. The T-allo10 product is a promising option for preventing GvHD but we would like to develop strategies to efficiently generate Tr1 cells in larger numbers (currently it is 10-15% of the T-allo10 product) and to track them inside the patient. To achieve this, we will define the unique features of the T-allo10 derived Tr1 cells. These data could increase the potency of the T- allo10 cell therapy and expand the use of allo-HSCT. In addition, they will lay the ground work for the application of T-allo10 therapy in other disease indications and immune disorders where fine-tuning of immune tolerance is required.
"Validation of a Novel Sensor to Quantify Blood Aldehydic Load in Humans"
Laboratory Based Investigator: Eric Kool, Chemistry
Clinical Based Investigator: Kenneth Weinberg, Pediatrics – Stem Cell Transplantation
Aldehydes are compounds involved in many intracellular metabolic processes. Reactive aldehydes induce DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway. Aldehydes are metabolized by the aldehyde dehydrogenase (ALDH) family of enzymes, and a highly prevalent mutation in ALDH2 causes the “Asian flushing syndrome”, which is associated with a variety of diseases including atherosclerosis and cancer. The range of human blood aldehyde levels and variation due to genetic mutations in ALDHs is unknown. Despite the important role of reactive aldehydes in human disease, few tests can quickly and accurately measure aldehyde levels in the body, and no tests are clinically available to measure aldehyde levels within cells, which presents a potentially useful diagnostic or prognostic biomarker. We have developed a novel system using a fluorophore and hydrazone transfer (“Darkzone”) reaction to rapidly detect and quantify intracellular aldehydes. We propose to adapt the innovative Darkzone sensor by optimizing and validating its use as a clinical assay in humans to provide the first description of this important class of compounds to human health.