Tissue Chips in Space 2.0: Translational Multi-Organ Tissue Chip Systems for Drug Efficacy, Toxicity Testing, and Personalized Medicine in Human Health, Aging and Associated Diseases (UG3/UH3 Clinical Trial Not Allowed)

RFA-TR-24-025

Research Objectives and Scope

This initiative supports translational research using tissue chips to investigate the effects of microgravity and the spaceflight environment on the human body. The findings will provide mechanistic insights into how the microgravity environment models aging and diseases associated with aging, particularly, but not exclusively, in integumentary, skeletal, muscular, nervous, endocrine, cardiovascular, immune, respiratory, digestive, urinary, and reproductive systems. Research designed to improve the translation of existing knowledge into strategies for the prevention and treatment of such diseases or conditions in humans will be responsive to this NOFO. Development of integrated complex organ system by using iPSC-derived organ-specific cell types from diverse groups of people is expected in this NOFO. A complex organ system may be a multi-organ or single organ MPS well mimicking organismal function, for example by introducing hormones or lymphokines/chemokines. Multi-organ Integrated MPS system may be a system comprised of more than one tissue/organ affected in healthy aging and age-related diseases. Multi-organ system can be comprised of individual organ/tissue integrated in one MPS, or co-culture of different organ/tissues including vascularization, innervation, incorporation of immune cells. This complex organ system should allow for modeling of aging and age-related conditions with higher precision.  Multi-organ signals are regulated during aging and aging-related changes in interorgan communication may play a significant role in aging pathology. In this multi-organ system, it is also of interest to assess any changes in the physical and functional characteristic of exosomes or extracellular vesicles as important mediators of intercellular signaling and communication under microgravity. Understanding the mechanisms that coordinate organ interactions may lead to new insights into multi-morbidities. Incorporation of population diversity in the MPS will allow for better understanding of the complexity and heterogeneity of aging and associated pathologies and will lead to better characterization of the hallmarks of aging, such as epigenetic alterations, changes in telomere length, shift in multi-omic (transcriptomic, proteomic, and metabolomic) profiles, post-translational modifications and dysbiosis. Cellular senescence may be triggering aging and could be considered as a therapeutic target for treating aging-related pathologies and chronic diseases, e.g., cancer, neurodegeneration, heart disease and osteoarthritis. The outcomes of this program will contribute to the development of senescence biomarkers and identification of therapeutic targets. 

The identification of targetable molecular pathways will contribute to facilitating translation into strategies for the prevention and treatment of aging-related conditions and diseases. It is anticipated that the funded projects will develop integrated automated and miniaturized MPS capable of functioning autonomously for extensive periods of time. These systems should be equipped with capabilities to maintain culture without external intervention and to be monitored remotely through real-time biosensing and readout capabilities, including telemetry operations. MPS will be subject to post flight recovery for tissue (e.g., histological) and multiomic (e.g., genomic, proteomic, metabolomic, epigenomic) analyses to elucidate the pathways affected by microgravity, to identify hallmarks of aging accelerated by the permanence in space, and to assess biomarkers of aging-related conditions. The newly acquired knowledge will enable novel pharmaceutical design/targets based on a better mechanistic insight of the biology.

Each UG3/UH3 application should be structured to meet the NIH/CASIS program goals. It is anticipated that the UG3 phase will involve on-ground development of multi-organ automated tissue chip technology to be used in microgravity environments. That includes, but it is not limited to, working with the ISS-NL and ISS-NL Implementation Partners to design, develop, and execute ground testing of flight hardware in pilot experiments to validate that all of the science objectives defined for the proposed experiment can be completed prior to flight integration for launch to the International Space Station and execution on orbit. Successful UG3 projects may transition into the UH3 phase for re-flight and more extensive experiments and analyses, with no more than 5 years of support for UG3/UH3 phases. The models are expected to recapitulate critical aspects of human physiology and to provide a measurable output for the representative systems. It is expected that iPSC from diverse groups of donors will be used in developing multi-organ tissue chips that will allow more accurately represent human physiology and pathology. Factors contributing to diversity that can influence the risk and likelihood of developing a disease, experiencing a long-term health outcome, and responding to treatment include (but are not limited to):

• Age
• Biological sex
• Pregnancy status
• Life experiences (negatives, such as psychosocial stress and lack of basic resources, or positives, such as educational and employment opportunities)
• Unhealthy behaviors (e.g., substance use, sedentary lifestyle, overeating, risky sexual activity)
• Health-promoting behaviors (e.g., adequate sleep, obtaining recommended preventive services, physical activity, healthy eating)
• Environmental conditions (e.g., pollution, access to health care or healthy foods, neighborhood segregation)
• Genetic variation and geographic ancestry
• Underlying medical problems or presence of comorbidities (i.e., additional diseases or conditions)

Essential characteristics of the models should include all or some of the following features: 1) multi-cellular architecture that represents characteristics of the healthy tissues or organs and their pathology; 2) functional representation of normal and diseased human biology; 3) reproducible and viable operation under physiological conditions maintained for extended periods of time; and 4) representation of diversity and heterogeneity of human population.  The platform used should be compatible for operation at the ISS-NL using ground-based controls, transmit to ground control assay outputs that include telemetry operation for different types of read-outs depending on particular multi-organ system architecture. The platform should also provide spatial and temporal control of the cellular microenvironment, while enabling continuous monitoring (sensing), probing (direct in-cell measurements), and sampling (testing and continuous data collection and analysis) of the system. Particularly, the monitoring of fluidic control, oxygen and pH in-line sensors is expected.

At least one flight opportunity is expected for each of the UG3 and UH3 phases, and therefore a flight experiment should be proposed for each of the UG3 and UH3 phases. Selected projects should be flight ready within 18 months of the specific award period, but it will not be possible to secure flight allocation resources on the International Space Station for all flight-ready projects in this time interval if multiple investigations mature at the same time.  If flight schedules change, investigators may modify proposed timelines, subject to review and approval by the NIH Program Officer in coordination with ISS-NL.

This application will be administered as a bi-phasic award.  The entire project period (combined UG3 and UH3) should not exceed five years. Applicants may propose a project period of up to two to three years for each phase depending on project needs. Please note below the major goals that are anticipated to be accomplished under each phase of award.   

Major Goals of the UG3 phase:

(1) develop complex-organ MPS system using iPSC-derived or primary patient cell sources on tissues/organ-on-chips platforms with platform integration to study organ pathology and organ-to-organ communication. Strong justification and rational for cell source used should be provided.  Models should demonstrate a functional representation of normal and diseased human states representing population diversity. These MPS systems should be developed to be functional in automatic regime for prolonged periods of time and be capable of telemetry for continuous monitoring of the system. These miniaturized systems should be capable of integrating with the flight-certified hardware for payload and functioning in an automatic regime. (2) determine the relevance of models via preliminary testing of key experimental features and outcomes on the ground and during the initial flight to the ISS-NL. The successful outcome will determine which UG3 projects will proceed to the UH3 phase of the study. This would include, for example, inclusion of non-invasive endpoints that generate reproducible data under physiological conditions over a prolonged culture conditions at the ISS-NL. The functional validation of the tissue chips may be model-specific.

Major Goals of the UH3 phase:

(1) to demonstrate the functional utility of the models for understanding the effects of microgravity on human physiology, (2) to correlate these effects with hallmarks of aging and markers of age-associated conditions, (3) to identify novel targets for drug screening, (4) to assess candidate therapies for efficacy and safety. These goals will lead to the establishment of pre-clinical foundations that will inform clinical trial design. To achieve this, the applications should focus on outcomes that may include:

• Cross-validation of model end-points with clinical measures in humans
• Characterization of the parameters of response to exposure to the space environment on the ISS-NL
• Developing translatable pharmacodynamics (i.e., target engagement) biomarkers for well-validated therapeutic targets
• Conducting preclinical efficacy testing of candidate therapeutics using innovative approaches, data acquisition and analyses
• Extensive characterization and clinico-pathological staging in the models with the corresponding stages of clinical disease using translatable biomarkers
• Developing strategies for rapid, open-access dissemination of data, and methodology, for rapid distribution of models for their use in a therapy development

Application budgets are limited to $750,000 direct costs per year.

September 16, 2024

October 18, 2024

Dmitriy Krepkiy, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Office of Special Initiatives
Phone: 301-451-2232
Email: dmitriy.krepkiy@nih.gov

Tiziana Cogliati, Ph.D.
National Institute on Aging (NIA)
Division of Aging Biology
Telephone: 240-397-4596
Email: tiziana.cogliati@nih.gov