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Long COVID Care Resources and Education to Advance Community Health (REACH)

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Agency for Healthcare Research and Quality (AHRQ)

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Long COVID affects millions of people in the U.S. and has disproportionately impacted vulnerable populations including low-income persons and communities of color who often face barriers to healthcare access. As trusted, accessible providers, federally-qualified healthcare centers (FQHCs) are well-positioned to help mitigate inequities by providing access to Long COVID care in their medically underserved communities. We propose that a care model, Long COVID Care Resources and Education to Advance Community Health (REACH) where a centrally-coordinated, multidisciplinary Long COVID hub program that supports and partners with networks of safety-net FQHCs in the community will help expand and improve the care of vulnerable patient populations suffering from Long COVID. The Stanford Long COVID hub program is a team-based multidisciplinary clinical and research program rooted in a primary care-specialty care partnership and, together with key community partners including Community Health Center Network and San Mateo Medical Center and others, our goal is to extend the reach of this program and expand access for vulnerable patients with Long COVID through the following specific aims: AIM 1: Improve community awareness and education on Long COVID for patients and clinicians. AIM 2: Support primary care providers in partner safety-net FQHCs by creating a collaborative learning community with peer-to-peer asynchronous and real-time consultation. AIM 3: Improve Long COVID care referral coordination and access at the Stanford hub clinic. Our approach is to build upon the evidence-based and well-established Chronic Care Model (CCM) with innovative components that are adaptive and responsive to the rapidly changing landscape of Long COVID care. We will implement the tiered educational outreach and peer-to-peer primary care support strategies across partnering FQHCs with synergistic expertise from our colleagues at the Evaluation Sciences Unit, Office of Community Engagement, and Center for Continuing Medical Education. We will utilize a stepped wedge design and evaluate the model with a formative and summative mixed-methods approach guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to assess overall project reach and impact and adapt strategies throughout the REACH project duration. As part of the cooperative, we will collaborate with AHRQ and other recipients in the Learning Community to share, incorporate, and disseminate learnings in a collective effort to support the primary care community in Long COVID education and management. Overall the goals are to expand access to comprehensive, coordinated, and person-centered care for vulnerable patients with Long COVID.

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Mentoring Emerging Researchers at CHLA (MERCH-LA)

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Beta cell dysfunction and death are significant pathologies underlying the development of Type 2 diabetes. There is both clinical and molecular evidence that the pathogenesis of COVID19 may have acute and specific effects on pancreatic beta cell function. One of the barriers to understanding how SARS-CoV2 infection may affect beta cell function and survival in patients is the limited number of physiologically relevant animal models to study. We have capitalized on unique access the pancreas of SCV2-innoculated animals to model and understand how SARS-CoV2 infection affects beta cell survival, metabolism, and function. There is controversy in the literature regarding if SARS-COV2 directly infects beta cells and affects beta cell function and survival or if the disruption of glucose homeostasis in patients is secondary. We hypothesize that SARS-CoV2 infection directly and acutely compromises beta cell function and survival by reprogramming cellular metabolism, thus leaving hosts susceptible to diabetes during or after infection. These highly innovative experiments capitalize on a unique and clinically relevant model system and employs cutting edge techniques to assess how beta cell survival and metabolism are affected by SARS-CoV2 infection. These experiments will provide critical mechanistic insight to the underpinnings of the emerging clinical phenotype of acute hyperglycemia, diabetic ketoacidosis, and potentially lifelong diabetes that may afflict a significant number of patients who have recovered from COVID19. The objective of this proposal is to protect the PI’s time to provide culturally-aware mentoring and intensive training to graduate students from historically underrepresented backgrounds participating in this innovative research program. This objective dovetails with the PI’s immediate and long terms goals, which are to: (1) establish MERCH-LA (Mentoring Emerging Researchers at Children’s Hospital Los Angeles) as a fundamental part of the educational and research infrastructure at CHLA and (2) longitudinally track and quantify outcomes for MERCH-LA graduates into bioscience-related post-graduate careers.

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Wastewater Sampling: A New Tool to Accelerate Ending the HIV Epidemic

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Current estimates are that 57% of persons in the U.S. with HIV are suppressed, leaving 43% unsuppressed, including about 13% who are undiagnosed and 30% who have been diagnosed but are not currently suppressed. Identifying persons with unsuppressed HIV to link them to care and antiretroviral treatment (ART) is critical for improving health and reducing new infections. New epidemiologic tools that identify in real time communities with high amounts of circulating HIV may enhance efforts to reduce HIV transmission and substantially contribute to ending the HIV epidemic. During the SARS-CoV-2 (SCV2) pandemic, we and others used “wastewater environmental virology” to monitor and respond to COVID. It uses viral capture and PCR detection of viral nucleic acid from wastewater collection sites to detect, quantify, and predict total SCV2 activity in time. We built a robust and mature wastewater sampling program for the Houston region that includes weekly assessment of 39 wastewater collection sites covering about 4 million residents. Our recent preliminary data demonstrate that HIV is detected in wastewater. Wastewater testing is unbiased, comprehensive, real-time, quantitative, and not influenced by access to health care, stigma or denial. We hypothesize that our pioneering wastewater sampling program can be applied as a powerful new tool to identify geographic areas with a high active burden of HIV, reflecting substantial numbers of people with undiagnosed or untreated HIV infection. Resources can then be mobilized to these communities to enhance HIV outreach, testing, prevention and linkage to care. The specifics aims are: 1) To develop a sensitive, reproducible, and streamlined wastewater HIV detection pipeline; 2) To develop epidemiologic models incorporating data from wastewater sampling as a novel and informative parameter along with routine surveillance data on HIV diagnoses and population data; 3) To characterize and incorporate stakeholder preferences, priorities, and recommendations for engaging key community stakeholders in the HIV wastewater sampling program with consideration to the ethical, legal, social, and cultural contexts of individuals living in target neighborhoods; 4) To determine if delivering proven public health interventions to neighborhoods as directed by wastewater data can reduce the wastewater viral load and increase HIV diagnoses in those neighborhoods. This research will enhance the Respond pillar of the End the HIV Epidemic (EHE) strategy. It will leverage and strengthen partnerships between the researchers and the Houston Health Department, the regional public health authority overseeing many EHE programs in Houston. The work in Houston, a high priority EHE region, will result in: (i) the US’s only HIV wastewater sampling program, (ii) epidemiologic models enhanced with wastewater data that identify unmet testing and treatment needs, (iii) community-informed and ethically appropriate, real-time public health monitoring that reduces the number of people with unsuppressed HIV, and (iv) tools and expertise that can be disseminated to other areas.

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Endothelial-Leukocyte Adhesion in CAR T Cell Treatment Associated Neurotoxicity

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This project studies the mechanism of neurologic toxicity in chimeric antigen receptor (CAR) T cell therapy. CAR T cells are genetically modified, patient derived T cells that use the CAR to recognize and destroy malignant target cells. Although CAR T therapy has shown impressive results against leukemia and lymphoma, approximately 30-40% of patients experience neurologic side effects in the first month after receiving CD19- targeted CAR T cells. This includes cognitive disturbances, seizures, and in rare cases fatal cerebral edema. Systemic cytokine release syndrome after CAR T cell infusion is a well-established risk factor for neurotoxicity, but the connection between systemic inflammation and brain dysfunction is poorly understood.  To study the mechanisms of neurotoxicity, we have developed an immunocompetent mouse model. After treatment with high dose CD19-directed murine CAR T cells, mice develop motor and balance difficulties, as well as brain microhemorrhages. Surprisingly, we found that >10% of cortical capillaries are obstructed by white blood cells during neurotoxicity. This was accompanied by capillary remodeling and decreased vessel coverage by pericytes. Based on these findings, we now propose the following experiments: Aim 1: What molecular mechanisms cause white blood cells to plug capillaries during neurotoxicity? We will use in vivo two-photon imaging in mice to determine which cell types cause the capillary plugging – the mouse’s own or the transferred CAR T cells? We will then measure how CAR T cell treatment changes the expression of adhesion molecules in brain capillary endothelial cells and in leukocytes, and test whether blockade of these adhesion interactions can prevent capillary plugging and neurotoxicity.  Aim 2: Is neuroendothelial-leukocyte adhesion increase in human microvessels during neurotoxicity? In parallel to our work in mice, we will use a 3D in vitro model of human brain capillaries to measure how soluble factors in patient plasma affect adhesion molecule expression in the endothelium. We will then test whether white blood cells from CAR T cell patients with neurotoxicity have increased predilection for plugging synthetic microvessels that mimic capillaries, and whether we can prevent this plugging by blocking adhesion molecules.  Aim 3: Can the strength of cell-cell adhesion signaling separate CAR T cell efficacy from toxicity? We will use quantitative multiplex immunoprecipitation to probe protein-protein interaction networks in CAR T cells that cause high or low neurotoxicity in mice to understand what activation states are conducive to neurotoxicity. We will then test whether knock down of adhesion molecule expression can direct CAR T cells away from a toxicity phenotype by impairing their ability to signal to other cells, and to adhere to the brain microvasculature.  This work is innovative because it combines advanced imaging, in vitro modeling techniques, and protein network analysis in a unique collaboration between neuroscience, vascular biology, and oncology. The work is significant because it addresses key safety issues in emerging cancer immunotherapy modalities.

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Convoy: A Cultural approach of Navajo Youth to Biomedical Sciences

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National Institute of General Medical Sciences (NIGMS)

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Summary: Project Title: CONVOY: A Cultural approach of Navajo Youth to Bio- medical Sciences. Need Assessment: STEM Learning Ecosystems are localized multi-stakeholder collaborative networks (MSCNs) that are “dynamic collaborations among schools, out-of-school time programs, STEM expert institutions (eg., museums, science centers, and institutions of higher education), the private sector, community-based organizations, youth and families”, and has been identified as one of the key sources to harvest human capital and contribute to novel interventions through the development of advanced knowledge. We will create a bridge between traditional indigenous knowledge and modern biomedical science via “CONVOY”. Peer Groups: Numerous peer groups focus on the development of K-12 and undergraduate research and education programs for underserved minority communities, but there are very few who are focusing on healthcare and biomedical sciences. This proposed activity will provide the students with health disparity-related research experiences, hands-on laboratory training, and other educational and communication opportunities via Science Café and Health Fairs to prepare them for future leadership and careers in healthcare, biopharma, and other associated professions. Proposal: “CONVOY” project will bring together students from Junior high schools, high schools (mentees) and Diné College (mentor avatars) in order to spawn their enduring curiosity in biomedical and health sciences — especially among Navajo (Diné) youth and students from other underserved communities— while adapting the concept of “near-peer” network to bring forward the local health issues to the open forums. Specific Aims: CONVOY, identifies causal links between Indigenous traditional knowledge and modern science to achieve four specific aims i.e., 1) Motivate Navajo high school and junior high school students to study and pursue careers in Biomedical Sciences and related fields; 2) Nurture holistic practices that bridge the gap between Navajo traditional practices and western medicine to develop a marketable land based solution, while focusing on problems faced by local communities; 3) Prepare students to enroll in institutions of higher learning and provide opportunities to earn college credit in high school through Dine College’s Dual Enrollment Program for biomedical sciences, and 4) Develop curriculum for a 10-week summer program to support activities by “CONVOY”. Expected Outcome: the benefits of the “Convoy” will include but are not limited to: i) Development of a need appropriate support system (near-peer-mentorship) that will serve as a main technical support for training and innovative research to help provide better healthcare services, ii) Greater understanding of the local epidemiology of infections, diseases and health disparities, iii) Increase local workforce development in several critical areas that have implications broader than current COVID-19 pandemic or other infections and diseases.

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Identifying patient subgroups and processes of care that cause outcome differences following ICU vs. ward triage among patients with acute respiratory failure and sepsis

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National Heart Lung and Blood Institute (NHLBI)

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Decisions to admit patients with acute respiratory failure (ARF) and sepsis (the most common and lethal cause of the acute respiratory distress syndrome) to intensive care units (ICUs) are highly variable across the US. And, yet, these triage decisions have a substantial impact on patient outcomes. In our prior work, we used detailed electronic health record (EHR) data from 9.2 million hospitalizations and found that decisions to admit ARF patients to wards were associated with a 3.8% absolute increase in mortality. In contrast, choices to admit sepsis patients to ICUs resulted in considerably longer length of stay and a 5.1% absolute increase in death. The nationwide impact of such discretionary triage would be exponentially greater. Our findings highlight tremendous opportunities to improve ARF and sepsis outcomes by identifying the patient subgroups and processes of care that most strongly contribute to the benefits and harms of ICU- versus ward-based care. This application proposes to update our ARF and sepsis cohort such that it includes all admissions from 2013 through 2022 across 29 hospitals in the Kaiser Permanente Northern California and University of Pennsylvania health systems, and incorporate more than 100 more data fields per patient. This curation of highly granular EHR data will enable us to identify the: (1) distinct patient subgroups and phenotypes among those meeting the syndromic criteria of `ARF' and `sepsis;' and the (2) processes of care and (3) inpatient complications that causally explain the observed associations of ICU vs. ward triage with patient outcomes. Our multidisciplinary team will apply diverse expertise in instrumental variable regression, mediation analyses, machine learning, complex EHR data, and probabilistic phenotyping to complete three aims that promote our long-term goal of improving care, and hence outcomes, for patients with ARF and sepsis regardless of where they are treated. Several methodological innovations will enable us to achieve these goals, and, in turn, to not only surmount key limitations of prior studies that sought to determine which acutely ill patients benefit from ICU admission, but identify the mechanisms underlying such triage effects. These data will also allow us to quantify the impact of COVID-19 on ICU and ward triage patterns, care processes, and outcomes among ARF and sepsis patients, thereby modernizing our results and enabling their applicability to pandemic eras. Completing the aims of this study will improve public health by identifying ways in which emergency departments, ICUs, and wards can improve outcomes for the more than 4 million Americans hospitalized each year with ARF and/or sepsis. Such results will enable development and testing of personalized triage algorithms, and guide optimal care for patients without always requiring ICU admission, thereby improving patient outcomes, reducing health care costs, and preserving ICU capacity for patients who truly need it.

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Oral mRNA Nanotherapy for Bleeding Disorder

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National Heart Lung and Blood Institute (NHLBI)

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Protein replacement therapy has been a cornerstone in treating genetic diseases (e.g., hemophilia) with loss or reduction of the function of a particular protein, by using recombinant proteins or recombinant engineered proteins. However, most protein therapeutics have short circulation lives, and thus require frequent invasive infusion to maintain their therapeutic efficacy. For example, the most common treatment for hemophilia A caused by a deficiency of blood clotting factor VIII (FVIII) is factor concentrate replacement, which is associated with burdensome frequent intravenous infusion. To address the unmet medical need of hemophilia, the major objective of this project is to develop a non-invasive oral mRNA delivery nanoplatform for durable protein replacement therapy requiring infrequent dosing. Synthetic mRNA has shown enormous potential for biomedical applications, with mRNA vaccines already clinically approved for COVID-19. Various delivery strategies have been developed to improve mRNA translation; however, an ongoing challenge of mRNA therapy is managing the transient efficacy due to its relatively short half-life, and oral mRNA delivery remains elusive. In my previous work, I have identified a unique poly(zwitterion)-lipid-based micelle platform that can cross the intestinal epithelial barrier and lead to a very potent oral bioavailability of biomolecules such as insulin. Recently, I have also discovered a new type of ionizable lipids that can extend the duration of mRNA-mediated protein expression. In this F32 project, I propose to combine the epithelium-crossing poly(zwitterion)-lipids and the unique ionizable lipids to develop an innovative mRNA delivery platform for oral, durable replacement therapy of bleeding disorders. In Aim 1, I will synthesize new poly(zwitterion)-lipids and ionizable lipids and generate a series of new mRNA lipid nanoparticles (LNPs), and systematically investigate their effects on oral transcytosis and the durability of protein expression in vitro and in vivo. In Aim 2, we will select the top-performing LNPs for oral delivery of FVIII mRNA and evaluate the FVIII mRNA nanotherapy in healthy and hemophilia mouse models. With the successful completion of this project, we expect that the oral durable mRNA delivery strategy will provide a more effective and robust therapy for hemophilia and other bleeding disorders.

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Biophysical, Structural, and Cellular Dissection of COPI-Dependent Retrograde Trafficking Using a Coronavirus Toolkit

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National Institute of General Medical Sciences (NIGMS)

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The secretory pathway is responsible for the biogenesis of soluble and membrane proteins involved in communication, energy transduction, nutrient uptake, and defense. These proteins are synthesized in the endoplasmic reticulum (ER) and then trafficked to Golgi and other organelles such as the plasma membrane. This trafficking causes ER stress by accidental exodus of ER-resident proteins such as UDP-glucuronyl transferases (UGT’s). These are type I membrane proteins (T1MP’s) responsible for modifications of lipid hormones and of analgesics acetaminophen and morphine. These ER-resident T1MP’s display a dibasic sequence (Lys-x-Lys-x-x or Lys-Lys-x-x; x=any amino acid) in their cytosolic tail for ER-retrieval by the coatomer protein I complex (COPI). The α and β’ subunits of this hetero-heptameric complex bind this dibasic sequence to initiate T1MP packaging into vesicles originating from post-ER compartments such as cis-Golgi. These COPI coated vesicles traffic and deliver the T1MP proteins back to ER to restore secretory balance. However, the atomic principles underlying T1MP binding, release, and selective interactions with α and β’COPI subunits are not well understood. This is a critical knowledge-gap as T1MP release and escape from COPI modulate T1MP trafficking, post-translational modifications, and T1MP functions. COPI dysfunction has been implicated in a variety of disorders related to development, auto-immunity, and cancers. Our long-term objective is to gain fundamental insights into COPI-dependent retrograde trafficking of T1MP’s and the underlying atomic-level factors responsible for COPI dysfunction in diseases. In this grant, we will elucidate mechanistic insights into COPI recruitment, release, and T1MP post-translational modifications utilizing the coronavirus (CoV) spike protein, a T1MP with a dibasic Lys-x-His-x-x sequence, as a new model system. This dibasic sequence ensures COPI-dependent retrograde delivery of the spike from Golgi to the viral progeny assembly site in ER-Golgi intermediate compartment (ERGIC). In Aim 1, we will elucidate the atomic details of conformational modulation of COPI-spike interactions. In Aim 2, we will determine the principles that govern release from COPI and subsequent post-translational modifications of the spike. In Aim 3, we will elucidate the atomic basis of COPI subunit selectivity for the spike protein. These investigations will expand on a toolkit of spike mutants with modified COPI interactions, as recently published by our group. We will integrate structural approaches in X-ray crystallography, NMR, and Rosetta modeling with biophysical tools and cellular assays of secretory trafficking to gain unprecedented insights into fine modulation and conformational regulation of COPI-spike interactions. The innovative use of the spike protein as a T1MP model system will yield novel insights into fundamental secretory trafficking. These data will simultaneously opening avenues for the development of targeted therapeutics for COPI-selective disorders and for a deeper understanding of CoV assembly and processing of CoV vaccines.

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NON-CANONICAL MECHANISMS FOR INTERFERON-LAMBDA REGULATION OF SARS-COV-2 INFECTION

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National Institute of Allergy and Infectious Diseases (NIAID)

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As the SARS-CoV-2 pandemic continues, a better understanding of the factors that regulate broadly protective immunity is needed. Interferon-lambda (IFN-λ) mediates antiviral protection against SARS-CoV-2 without causing overt pathology and exacerbated disease. As such, recombinant IFN-λ is in clinical trials as a therapeutic for COVID-19. However, the endogenous role for IFN-λ in regulating infection and functions in preventing disease beyond antiviral programming during SARS-CoV-2 remain unknown. Our preliminary data show that mice lacking the IFN-λ receptor (Ifnlr1-/-) have increased illness and viral burden during SARS-CoV-2 infection without alteration of canonical antiviral gene induction associated with IFN. Instead, IFN-λ positively regulates the induction of CD8 T cell immunity, a cellular immune response critical to mediating protection against virus infection when neutralizing antibody responses are avoided. We further identified upregulation of cell cycle repair and proliferation genes associated with fibrosis in Ifnlr1-/- mice. This proposal will investigate these newly identified non-canonical functions of IFN-λ in regulating immunity against SARS-CoV-2 with the goal of informing therapeutic use of this cytokine.

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Somos Esenciales: Community Revitalization and Health through Latino Arts and Entrepreneurship

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Somos Esenciales: Community Revitalization and Health through Latino Arts and Entrepreneurship is a comprehensive community revitalization plan led by Cultura y Arte Nativa de Las Americas (CANA) in San Francisco’s Mission District in collaboration with government and community partners, that targets upstream social and policy determinants of health. Structural targets include combining an affordable housing/home ownership initiative, urban gardening and food distribution, harnessing economic development through transforming empty storefronts with Latino entrepreneurship, and providing culturally responsive wellness and mental healthcare. These efforts are a clear continuation and extension of CANA’s work and mission, critical for mental health (e.g., depression and anxiety), physical health (e.g., chronic illnesses such as hypertension, diabetes) and economic well-being of our families and community in a post COVID-19 recovery environment. Central to this collaborative plan is a community-based participatory action research approach with local Latino laborers, domestic workers, and cultural producers, in collaboration with professional health services researchers at UCSF, whose goal together is to identify the relationship between systemic inequities, racial disparities, and physical and mental health outcomes. CANA and its partners will utilize this research as part of the NIH Common Fund launched by the Community Partnerships to Advance Science for Society, and to create and implement a multi-platform COVID-19 recovery plan and community revitalization for Latino, Indigenous, and Black residents of San Francisco’s Mission District that brings opportunities for all to thrive through community revitalization and structural interventions focused on home ownership, food access, bilingual health and wellness, and economic workforce development.