OBJECTIVES/GOALS: Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease of lung scarring. Aberrant vascular remodeling is a contributor to IPF progression. We have identified CCN3 as an endothelial gene that is upregulated in resolving but not in persistent lung fibrosis in mice. Here we tested the role of CCN3 in lung microvascular endothelial function. METHODS/STUDY POPULATION: RNAi loss of function experiments were used to evaluate the role of CCN3 in lung endothelial biology. Human lung microvascular endothelial cells (HLMECs) were transfected with human CCN3 siRNA and analyzed via qPCR to assess expression of endothelial transcripts, via wound healing assay for assessment of migratory function, and via 2D tube formation assay for assessment of angiogenic function. To ascertain the effect of HLMECs on Normal Human Lung Fibroblasts (NHLFs), conditioned media (CM) from endothelial cells with control and CCN3 siRNA was applied to TGFβ primed fibroblasts and qPCR was used to measure expression levels of pro-fibrotic transcripts. Recombinant human CCN3 protein was subsequently used to confirm the gain of function role of CCN3 in lung endothelial biology using a subset of these assays. RESULTS/ANTICIPATED RESULTS: CCN3 is a secreted matricellular protein thought to be involved in angiogenesis, cell adhesion, cell migration, and inflammatory responses in endothelial cells. In other organs, CCN3 suppresses expression of fellow matricellular protein, CCN2 (CTGF); importantly, CCN2 is a known pro-fibrotic mediator of aberrant tissue remodeling in the fibrotic lung. Upon CCN3 knockdown in HLMECs, we observed reduced transcripts for inflammatory and pro-fibrotic genes, along with impaired endothelial function in wound healing and angiogenesis assays. CM from CCN3 knockdown endothelial cells enhanced the pro-fibrotic effects of TGFβ in NHLFs. Addition of recombinant CCN3 to HLMECs generated, conditioned media that reduced fibroblast pro-fibrotic activation. DISCUSSION/SIGNIFICANCE: We have shown that matricellular protein- CCN3 plays a fundamental role in endothelial identity and function and could be a promising therapeutic target in IPF. A future goal is to restore levels of genes such as CCN3 in the aged vasculature in the setting of lung fibrosis to test their capacity to promote vascular repair and fibrosis resolution.

OBJECTIVES/SPECIFIC AIMS: Acute myeloid leukemia (AML) is a devastating hematologic malignancy wherein <20% of patients will survive 5 years after diagnosis. In an effort to understand alterations that drive AML development and progression, The Cancer Genome Atlas detailed the most common recurrent mutations. One gene of interest identified here was HNRNPK, supporting our clinical observations that suggest altered expression levels of HNRNPK and its corresponding protein (hnRNP K) may impact AML. Here, we aim to elucidate the impact of hnRNP K overexpression in AML by utilizing AML cell lines and mouse models reflective of the human disease. METHODS/STUDY POPULATION: We utilized fluorescence in situ hybridization (FISH), qRT-PCR, and reverse phase protein array (RPPA) to evaluate HNRNPK copy number and expression levels in AML patient samples compared with CD34+ cells from healthy human donor bone marrow. Kaplan-Meier survival analyses were performed using clinical data from 415 AML patients at MD Anderson Cancer Center and stratified based on hnRNP K protein expression as evaluated by RPPA. To directly evaluate the impact of hnRNP K overexpression in vivo, we created 2 distinct lines of Hnrnpk transgenic mice (HnrnpkTg). Phenotypic differences in the hematologic compartments of these mice were evaluated via flow cytometry, immunohistochemistry, and transplantation assays. Molecular pathways have been evaluated in mice and cell lines using immunoblotting, qRT-PCR, and RNA-immunoprecipitation. The drug JQ1 was used in vitro with both OCI-AML3 cell lines and with primary bone marrow and splenocytes from HnrnpkTg mice. RESULTS/ANTICIPATED RESULTS: FISH analyses demonstrated that a large proportion of AML cases had amplification of HNRNPK that corresponded with upregulation of HNRNPK at the RNA and protein levels. Indeed, patients with high levels of hnRNP K had decreased overall survival compared with those expressing lower hnRNP K levels. In line with these clinical observations, we observed altered myelopoiesis in HnrnpkTg mice. These mice demonstrate increased CD11b+Gr1+ populations in the bone marrow and peripheral blood. Indeed, these mice develop myeloid leukemia, indicated by >20% of circulating white blood cells harboring markers of immature stem cells in conjunction with positive myeloperoxidase staining and blast-appearing morphology. RPPA revealed expression of c-Myc positively correlated with increased hnRNP K levels. In HnrnpkTg mice, c-Myc protein was increased, yet MYC RNA was invariably decreased compared to wildtype. To decipher a mechanism by which this may occur, we demonstrated a post-transcriptional interaction between hnRNP K and c-Myc in vivo. JQ1, a BRD4 inhibitor, that epigenetically decreases c-Myc expression showed preferential activity against myeloid cells expressing high levels of hnRNP K both in vitro and in vivo. DISCUSSION/SIGNIFICANCE OF IMPACT: These preliminary studies demonstrate that hnRNP K overexpression causes myeloid malignancies in both mouse and man. We have determined that c-Myc contributes in part to hnRNP K-mediated leukemogenesis, and that targeting c-Myc may be an effective strategy for hnRNP K-overexpressing AML. We are currently validating other potential targets for interaction with hnRNP K by performing RNA-Seq and hnRNP K immunoprecipitation followed by mass spectrometry. Fortunately, several of our putative targets are druggable—allowing for viable translational outputs to these mechanistic studies.

OBJECTIVES/GOALS: The project goal was to conduct formative work using community-based participatory research (CBPR) to inform the development of a laundromat-based reproductive health literacy intervention (LI)informed by Passhe-Orlow and Wolf’s Conceptual Model. We provide insights to support the development of similar health literacy interventions. METHODS/STUDY POPULATION: In Phase I, we recruited female patrons over the age of 18 living in DC from 4 community laundromats. Participants completed a survey with validated measures to assess reproductive health knowledge, self-efficacy, and intentions to seek care. Open-ended questions assessed participants’ experiences accessing care, communication with health providers, and laundromat use. Data informed the development of a 2-3 minute reproductive health literacy intervention (LI) storyboard. In Phase II, in-depth interviews were conducted with reproductive health providers (midwives, obstetricians-gynecologists, women’s health registered nurses, women’s health nurse practitioners) working in the communities where the laundromats are located. LI acceptability and appropriateness were explored. RESULTS/ANTICIPATED RESULTS: For Phase I, we recruited 60 patrons. Participants (68.3%) expressed interest in a laundromat-based reproductive health literacy intervention (LI). Identified reproductive knowledge gaps included: unaware of fertile days (50.0%); believe prenatal care should begin after 2nd trimester of pregnancy (50.0%); unclear about pregnancy spacing (85.0%); unable to identify use for folic acid (91.7%); believe once a cesarean always a cesarean (53.3%). In Phase II, all 14 providers supported increasing community accessibility to health information: “we have to move beyond doing public health education in a provider’s office. That’s very outdated.” Providers identified the LI as an approachable, informative, and accessible way to disseminate health information. DISCUSSION/SIGNIFICANCE: Patron and provider input informed our choice of content, style, and delivery of the reproductive health literacy intervention. An essential aspect of our CBPR approach, this research will inform effective, appropriate reproductive health education despite barriers presented by access, transportation, and work schedules.

OBJECTIVES/GOALS: Community Engagement Advisory Boards (CEAB) serve as a vital resource for engaging and partnering with communities in research. The purpose of this project is to describe the perspectives of members of a long-standing CEAB in providing input and promoting research that aligns with the needs, experiences, and concerns of the communities they represent METHODS/STUDY POPULATION: Three 90-minute focus groups were conducted with a subset of a CEAB(n=17)(M years spent with CEAB =7.3) affiliated with the Center for Clinical and Translational Science at the University of Illinois-Chicago. Members areas of expertise include perspectives from faith-based organizations, community organizing, public health and working with diverse populations. Transcribed audio recordings of the focus groups were coded using thematic analysis wherein two authors coded independently, followed by audited discussion and final consensus codes. Main themes were identified after reviewing final codes. RESULTS/ANTICIPATED RESULTS: CEAB members described the bi-directional nature of their role serving as a conduit between research institutions and their communities, identified strategies to promote research literacy in communities, called for researchers to take a proactive approach in forming and sustaining community partnerships, and helped identify opportunities to promote community engagement in more creative and feasible ways. Additionally, CEAB members identified perceived opportunities for the board as a whole to be more involved in Chicago communities to further their role as a liaison between the university and the community. DISCUSSION/SIGNIFICANCE: These findings may have implications for investigators to better address community priorities in research by understanding unique local realities as well as help other CTSA hubs’ to leverage their communities’ expertise.

OBJECTIVES/GOALS: Sexual minority men (SMM) of color are at greater dementia risk than their White and non-SMM counterparts. The purpose of this study is to examine the relative effects of ethnoracial minority status, sexual minority status, and the intersection of both on dementia risk for men in the U.S. using subjective cognitive decline (SCD) as a proxy for dementia. METHODS/STUDY POPULATION: Data will be weighed to represent population estimates from 35 states’ 2019-2022 Behavioral Risk Factor Surveillance System Survey to describe SCD among 4 study groups consisting of SMM and non-SMM who are from minoritized ethnoracial groups (i.e., minoritized ethnoracial gay and bisexual men, minoritized ethnoracial heterosexual men), and White SMM and White non-SMM (i.e., White gay and bisexual men, White heterosexual men) aged ≥45 years. Logistic regressions and adjusted odds ratios will determine SCD prevalences and test for differences between prevalence and demographic characteristics (i.e., education, employment, income, marital status, health coverage, and depression). RESULTS/ANTICIPATED RESULTS: Due to excess chronic stress from belonging to multiple intersecting marginalized identities, we expect that SMM from minoritized ethnoracial groups will have a greater prevalence and higher odds of SCD after accounting for demographic factors when compared to groups that benefit from both “White Privilege” and heterosexism (White non-SMM, White SMM, and minoritized ethnoracial non-SMM). We also expect the odds of SCD to be higher in minoritized ethnoracial SMM when compared to White non-SMM and minoritized ethnoracial non-SMM. The odds of SCD are expected to be higher in White SMM compared to White non-SMM. DISCUSSION/SIGNIFICANCE: This is the first population-based study to apply an intersectional lens to examine dementia risk across the axes of race, sexual orientation, and gender identity. Findings from this study can inform targeted interventions to address the needs and experiences of LGBTQ+ subgroups at risk or living with dementia.

OBJECTIVES/SPECIFIC AIMS: Innovation in healthcare is increasingly dependent on technology and teamwork, requiring effective collaboration between disciplines. Through an intensive team-based competition event, Mount Sinai Health Hackathon 2017, aimed to harness the power of multidisciplinary and transdisciplinary collaboration to foster innovation in the field of cancer. Participants were immersed in an intensive weekend working in teams to develop technology solutions to important problems affecting patients and care providers in the field of cancer. The learning objectives were to enable participants to: Identify cancer-related healthcare problems which lend themselves to technology-based solutions. Delineate key behaviors critical to multidisciplinary team success Identify optimal strategies for communicating in multidisciplinary teams. Engage and inspire participants to apply knowledge of technology to meaningfully impact clinical care and well-being. METHODS/STUDY POPULATION: The Mount Sinai Health Hackathon is an annual 48-hour team-based competition, using a format adapted from guidelines provided by MIT Hacking Medicine. The 2017 event gathered a total of 87 participants (120 registered), representing 17 organizations from as far away as California, with a diverse range of backgrounds in bioinformatics, software and hardware, product design, business, digital health and clinical practice. The overall participation model included: Phase 0: Health Hackathon 101 summer workshops; Phase 1: pre-Hackathon priming activities using online forums Trello and Slack; Phase 2: a 48-hour onsite hackathon to catalyze innovation through problem sharing, solution pitches, team formation and development of prototype solutions; Phase 3: competitive presentations to judges and prize awards; Phase 4: a suite of post-hackathon support to stimulate continued development of innovations. The event sponsored by ConduITS, was also co-sponsored by Persistent Systems, IBM Watson, Tisch Cancer Institute, Sinai AppLab, Sinai Biodesign and other ISMMS Institutes. Mentors circulated throughout the event to support the teams in the technical, clinical, and business development aspects of their solutions. In total, the 14 teams formed during the Hackathon, created innovations ranging from diagnostic devices, networking apps, artificial intelligence tools, and others. The top 3 teams were each awarded $2500 to support their projects’ future development. RESULTS/ANTICIPATED RESULTS: Qualitative and quantitative post-event survey data revealed the Hackathon experience fostered collaborative attitudes and a positive experience for participants, providing insight into the potential benefits of team science. In the post-event survey (n=24) 92% of participants reported that the experience increased their ability to solve problems and 96% made new professional or personal connections. In addition, 96% of respondents would attend future Hackathon events and 75% reported they were likely to continue working on their project after the Hackathon. Qualitative feedback from 1 participant reported it was: “a wonderful event that really highlighted how much interdisciplinary team science can achieve.” Along with intermediate support interactions, including the winning teams participating in a Shark Tank style event with pitches to external entrepreneurs and investors, all teams will be followed up in 6 months time to determine if participants continue to work on projects, file new patents, create new companies, or leverage the new connections made through the Health Hackathon experience. DISCUSSION/SIGNIFICANCE OF IMPACT: Our experience indicates that a Health Hackathon is a compelling and productive forum to bring together students, trainees, faculty, and other stakeholders to explore tech-based solutions to problems in cancer and other areas of biomedicine. It is a valuable tool to foster collaboration and transdisciplinary team science and education. Follow-up analysis will determine to what extent the Mount Sinai Health Hackathon is contributing to an ecosystem that encourages professionals and trainees in healthcare and in technology development to work together to address unmet needs in healthcare with innovative technology solutions.

OBJECTIVES/SPECIFIC AIMS: The study aims to develop and test a biocompatible 3D-printed IVRs for the mechanical and release properties of a model drug, β-estradiol, then translate these methods to the target drug, progesterone. The goals include demonstrating decoupling of mechanical and release properties of the rings, release profiles driven by geometry and efficacy in sheep animal models to evaluate device safety. METHODS/STUDY POPULATION: A novel 3D-printing platform, continuous liquid interface production (CLIP), pioneered by Carbon, enables the fabrication of complex designs on a timescale that is amenable to manufacturing. The process utilizes computational-aided design (CAD), specifying shape and geometry, which is recreated via a photopolymerization process. IVRs are fabricated with CLIP using a biocompatible resin at a rate of approximately 15 min. per ring. Rings were fabricated and assessed for the release of a model drug, β-estradiol. The process was then translated to the target drug, progesterone. Rings were evaluated for radial compression and in vitro release in simulated vaginal fluid (SVF). RESULTS/ANTICIPATED RESULTS: Intravaginal rings (IVRs) were designed and fabricated to be geometrically complex in an effort to control release. Ring geometry and subsequent pore size was achieved through the use of unit cells. Several design parameters were explored including unit cell type, size, and band presence in two resins of differing mechanical properties. Through design, a wide range of radial compressive properties were achieved which spanned values covered by commercially available rings. The release of β-estradiol in SVF was found to span 57 – 115 days and resulted in near or complete release of the total loaded drug. Changing the internal geometric design of the ring was found to have minimal influence on the compression properties, thus the mechanical and release characteristics of the rings were largely decoupled. DISCUSSION/SIGNIFICANCE OF IMPACT: This is a novel approach to the design and fabrication of intravaginal rings for the treatment of infertility. The use of CAD and the decoupling of release from mechanical properties allows for us to move away from the one-size one-dose fits all approach to IVRs.

OBJECTIVES/GOALS: This community-engaged study explores Community Health Workers (CHWs), perspectives on i) barriers to cervical cancer screening and ii) the acceptability and feasibility of CHW-facilitated HPV self-sampling as a means of reducing existing cervical cancer disparities. METHODS/STUDY POPULATION: Semi-structured in-depth interviews were conducted with 15 CHWs in 2021 to gain insights into barriers to cervical cancer screening and the acceptability and feasibility of CHW-facilitated self sampling in their communities. Recruitment began in Lake County then expanded to East Chicago after initial interviews revealed that some community members seek care in this area. An IRB approved email was sent out to community partners’ mailing lists inviting CHWs to join a 30–60 minute interview. Participants received a $25 electronic gift card as compensation. Interviews were audio recorded, transcribed and then analyzed by the study team, using a combination of inductive and deductive coding. The Socio-Ecological Model was used as a guiding framework to analyze multilevel barriers and facilitators to screening. RESULTS/ANTICIPATED RESULTS: CHW-facilitated HPV self-sampling shows promise of mitigating (without eliminating) several existing barriers to cervical cancer screening, with six key considerations. Privacy (for most), time saved, and comfort were perceived to be major facilitators for acceptability, with concerns about the novelty of this approach, trust in provider (as opposed to CHW) expertise, and lack of privacy at home (for some) emerging as barriers. In terms of feasibility, synergies with existing CHW work, and some community members’ prior experience with self-sampling were found to be facilitators, with CHW’s self-efficacy in providing adequate support and limited time constituting areas of concerns for feasibility. Considerations for adoption included CHW training, gender concordance, safety and respect, among others. DISCUSSION/SIGNIFICANCE: In light of national calls to engage CHWs in screening delivery and leverage self-sampling, this study provides CHW perspectives as key stakeholders on a screening model that directly engages them, providing insights that can inform successful implementation to increase screening in Lake County and similarly underserved contexts in the US.

Objectives/Goals: Increasingly, women and people of color are earning PhDs. However, historically underrepresented (HU) degree seekers often follow a “nontraditional” track, pursuing their degree part time, at an older age, and balancing work and family with their studies. Over half of the U.S. PhD students are part time, a feature correlated with candidate diversity. Methods/Study Population: To address this need, the Advancing Diversity and Equity in Pre-doctoral Trainees (ADEPT) program was developed for part-time HU students who do not meet the requirements of the NIH-funded NRSA TL1 program but who offer relevant work and life experience. The program provides individualized navigation and tailored support based on individual student need and career goals, flexible training opportunities, and intentional connections to established, dedicated, and well-trained mentors throughout the predoctoral journey. To better understand their unique needs, we conducted thematic analysis on the notes taken during monthly meetings to explore the challenges our students face and how ADEPT provides support in navigating these challenges. Results/Anticipated Results: Students pursuing a PhD on a part-time basis while balancing other responsibilities, such as caretaking or a full-time job, bring a unique perspective to their graduate education. 5 ADEPT students described how their background or clinical work experience played a crucial role in their decision to pursue a PhD. Themes from the monthly meeting and mentor meeting notes include the challenges of balancing full-time jobs with school, and how they do not experience the cohort effect that a traditional, full-time PhD student would have as a resource. The students reflected on how an individualized culturally sensitive approach was instrumental to their success. Discussion/Significance of Impact: It was initially believed that part-time PhD students were rare. Despite this misconception, we easily recruited students. Students reported their experiences do not reflect the experiences of their full-time peers and their difficulty establishing a peer group, demonstrating the clear need for ADEPT.

OBJECTIVES/GOALS: A functional precision medicine platform to identify therapeutic targets for a glioblastoma patient with Li Fraumeni syndrome was performed. Comparative transcriptomics identified druggable targets and patient derived organoids and a 3D-PREDICT drug screening assay was used to validate the pipeline and identify further therapeutic targets. METHODS/STUDY POPULATION: A comparative transcriptomics pipeline was used to identify druggable genes that are uniquely overexpressed in our patient of interest relative to a cancer compendium of 12,747 tumor RNA sequencing datasets including 200 GBMs. Mini-ring patient derived organoid-based drug viability assays were performed to validate the comparative transcriptomics data. Additionally, a spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. RESULTS/ANTICIPATED RESULTS: Using comparative transcriptomics STAT1 and STAT2 were found to be significantly overexpressed in our patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. Druggable pathways predicted using comparative transcriptomics corresponded with ruxolitinib sensitivity in a panel of patient derived organoids screened with this compound. Cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. Additionally, 3D-PREDICT screening identified the mTOR inhibitor everolimus as a potential candidate. These two targeted therapies were selected for our patient and resulted in radiographic disease stability. DISCUSSION/SIGNIFICANCE: This research illustrates the use of comparative transcriptomics to identify druggable pathways irrespective of actionable DNA mutations present. Our results are promising and serve to highlight the importance of functional precision medicine in tailoring treatment regimes to specific patients.

OBJECTIVES/SPECIFIC AIMS: Since 1971, Naloxone has been the only FDA approved opioid antagonist indicated for use after opioid overdose. New formulations of Naloxone have been introduced into the market, including an injectable, auto-injector, and nasal spray. However, Naloxone is short-acting and as such often requires multiple doses and may induce severe withdrawal symptoms. This study examines the regulatory framework to understand the evolution of products indicated to treat opioid overdose and the landscape of therapies in development. Furthermore, this study examines how the Food and Drug Administration (FDA) and other government agencies have approached the opioid crisis. METHODS/STUDY POPULATION: A PubMed search of “naloxone AND opioid overdose” with the filter “humans” was conducted to understand Naloxone’s regulatory framework. The term “naloxone” was searched on the Drugs@FDA: Approved Drug Products database. Additionally, “nalmefene” was searched on ClinicalTrials.gov. To examine the opioid antagonist market landscape, a PubMed search of “opioid antagonist AND opioid overdose” with the filters “humans” and “clinical trial,” and a ClinicalTrials.gov search of “opioid antagonist and opioid overdose,” were conducted. Government agency reports were reviewed and cataloged. RESULTS/ANTICIPATED RESULTS: Preliminary findings suggest a lack of innovation in the development of novel opioid antagonists. Most literature review findings focused on already-marketed Naloxone products, including the original injectable approved in 1971, the 2014 Evzio Auto-Injector, and the 2015 Narcan Nasal Spray (Figure 1). For example, there were 14 results yielded from the FDA approvals database, but none of these results represented a new opioid antagonist molecule. A longer-acting opioid antagonist, Nalmefene injectable, was approved in 1995 but has since been removed from the market due to low sales. Our initial ClinicalTrials.gov search using condition “opioid overdose” and other terms “opioid antagonist”,revealed no new studies being conducted on alternative opioid antagonist treatments for opioid overdose. Findings only focused on the distribution, co-dispensing, intervention, pharmacokinetics/pharmacodynamics (PK/PD) of Naloxone (Figure 2). However, a Google search yielded one new trial with an opioid antagonist by Opiant Pharmaceuticals, almost fifty years after FDA’s approval of Naloxone. A ClinicalTrials.gov search was then performed using the search term “nalmefene” to find whether Opiant Pharmaceuticals’ trial was in the ClinicalTrials.gov database. However, the Opiant trial is phase I, and as such does not require reporting on ClinicalTrials.gov. In 2017, the National Institutes of Health (NIH) launched an initiative for longer-acting opioid antagonist formulations. In 2018, Opiant Pharmaceuticals announced positive phase I results for intranasal Nalmefene. The potential return of Nalmefene in intranasal form may play a significant role in reducing overdoses, especially in cases where a longer-acting opioid antagonist is necessary. Opiant Pharmaceuticals’ trial commenced after the NIH announced their initiative; furthermore, the NIH’s National Institute on Drug Abuse granted the company $7.4 million to further the investigation of this drug. We will continue to research drugs that have previously been studied for the indication of treating opioid overdose in the United States and abroad and catalog them. DISCUSSION/SIGNIFICANCE OF IMPACT: The abuse and misuse of opioids in the United States has caused an epidemic accounting for over 115 opioid-overdose deaths each day, devastating our nation, both socially and economically. The United States spends $78.5 billion annually to combat the misuse of these drugs. Due to the severity of the opioid crisis, efforts to better understand approved therapies and investigational products in development to treat opioid overdose will be of significance moving forward. This research can inform agencies who are developing strategies to reduce opioid overdoses and pharmaceutical product developers about the current opioid antagonist landscape.

OBJECTIVES/GOALS: The goal of this study was to understand the impact of a high sodium diet on gene networks in the kidney that correlate with blood pressure in female primates, and translating findings to women. METHODS/STUDY POPULATION: Sodium-naïve female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 beta-estradiol, and ultrasound-guided kidney biopsies for RNA-Seq were collected at the end of each diet. Blood pressure was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. Weighted gene coexpression network analysis was performed on RNA-Seq data to identify transcripts correlated with blood pressure on each diet. Network analysis was performed on transcripts highly correlated with BP, and in silico findings were validated by immunohistochemistry of kidney tissues. RESULTS/ANTICIPATED RESULTS: On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Cell type composition of renal biopsies was consistent among all animals for both diets. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. DISCUSSION/SIGNIFICANCE: Previous studies in primates to identify molecular networks dysregulated by HS diet focused on males. Current clinical guidelines do not offer sex-specific treatment plans for sodium sensitive hypertension. This study leveraged variation in BP as a first step to identify correlated kidney regulatory gene networks in female primates after a HS diet.

OBJECTIVES/SPECIFIC AIMS: Opinions regarding translational science vary incredibly. We aimed to gather a baseline of perceptions, barriers, and needs for translational science among faculty investigators. We will use these data to define areas in which the Duke Multidisciplinary Education and Research in Translational Science program (MERITS) can work to address, educate and improve. METHODS/STUDY POPULATION: Data was collected via a scalar, multiple-choice, open-ended survey including questions regarding, definition, impact, barriers, resources, and training preferences specific to translational science. Digital survey links were emailed to Duke University faculty. RESULTS/ANTICIPATED RESULTS: In total, 350 responses were collected. While perceptions of translational science varied, common defining elements were noted, including multidisciplinary collaboration (69%) and transitions between research stages (63%). Translational science was said to have an overall positive impact, despite 37% of participants stating issues of insufficient institution-wide support and 62% citing minimal training in translational science skills. DISCUSSION/SIGNIFICANCE OF IMPACT: Effective support for translational science requires a multi-faceted approach, as perceptions differ among investigators and between career stages. Duke MERITS will seek to standardize education and support ranging from teambuilding to entrepreneurship, and to promote support from institutional leadership to reduce barriers and facilitate acceleration of translational science.

OBJECTIVES/SPECIFIC AIMS: Unlike the high cure rates (90%) of children with acute lymphoblastic leukemia (ALL), that of adults is still lagging behind and better therapies are needed. Maternal embryonic leucine-zipper kinase (MELK) is aberrantly upregulated in cancer, and implicated in cancer stem cell survival. A recent study has identified FOXM1, a MELK substrate, as a therapeutic target in B cell ALL (B-ALL). Thus, we hypothesized that MELK may act as a therapeutic target in ALL via targeting FOXM1 activity. METHODS/STUDY POPULATION: Western blot and qPCR were used to assess MELK expression in 14 ALL cell lines. Knock-down and kinase inhibition approaches targeting MELK expression and function, followed by CCK-8 and Annexin V (flow cytometry) assays to measure cell viability and apoptosis, respectively. RESULTS/ANTICIPATED RESULTS: MELK was significantly upregulated in patients with ALL (oncomine data analysis). MELK was also significantly higher in B-ALL and T-ALL cell lines compared with that in blood cells of healthy donors. MELK knock-down significantly decreased cell viability (40%–70%, p<0.05, Fig. 1) in ALL cells, and induced apoptosis (~40%). OTS167, a potent MELK inhibitor exhibited cytotoxic activities in both B and T-ALL cells. The IC50 of OTS167 ranged from 20 to 60 nM; we also found a significant increase in apoptosis (p<0.05). Mechanistically, MELK inhibition resulted in decrease of FOXM1 protein levels 3 hours post-treatment. DISCUSSION/SIGNIFICANCE OF IMPACT: MELK is highly expressed in ALL and represents a novel therapeutic target likely via modulating FOXM1 activity. Functional and mechanistic studies will complement and ensure the success of the undergoing Phase I/II clinical trial of OTS167 in patients with refractory or relapsed AML, ALL, and other advanced hematologic malignancies.

ABSTRACT IMPACT: This presentation highlights an integrated curriculum in CTR and a scientific entrepreneurship approach to entice and support students and faculty in HP programs into CTR and SE thus expanding the pool of new minority CTR researchers. OBJECTIVES/GOALS: To present the TVMSC as a hub for trainings, mentoring programs, courses, entrepreneurship and support activities for health professionals(HP) and HP students :graduate (GS) and UgS and UgF. Responding to the need for CTR minority researchers, in a virtual setting due to COVID-19 crisis. METHODS/STUDY POPULATION: TVMSC will offer an educational program based in the Center for Research,Entrepreneurship and Scientific Collaboration (CRESCO) with on line courses and workshops in CTR and SE, for HP and students and a continued education curriculum for HP and clinician scientists toward a certification in CTR. Two hands-on experiences: a) a Pilot project program(PiP) with teams composed of an F, that previously completed training cycles and a research experience from a previous project in CTR as PI, with a research mentor and students or an established researcher as a PI with UgS and UgF, and b) participation in a SE team which will engage in training and submission of an SE project proposal. RESULTS/ANTICIPATED RESULTS: By the end of the five-year period the project will have had 200 UgS, 200 GS and 200 F that received online assistance in CTR skills, statistics and SE; 48 UgS and 48 GS with the skills in SEFL. In curricular development the project expects to have 6 online tutorials created, one FLSE online course and 18 modules in CTR content areas available for continued education of HP. Certifications in CTR will be completed by 160F/HPs. The expected participation in CTR on-hands experiences is 32 F, 64 students and 32 established researchers. PiP teams will publish at least 8 scientific papers and SEFL teams will submit at least 5 SE project proposals and 100% increase in CRESCO web based resources DISCUSSION/SIGNIFICANCE OF FINDINGS: This Project and its expected results will provide students and faculty members island-wide with the knowledge, skills and experiences in CTR with IE approach to foster the expansion of a cadre of Hispanic minority CTR researchers in direct benefit of the health of the people of Puerto Rico.

Social determinants of health affect clinical and translational research processes and outcomes but remain underreported in empirical studies. This scoping review examined the rate and types of social determinants of health (SDoH) variables included in the JCTS translational research studies published between 2017 and 2023 and included 129 studies. Most papers (91.7%) reported at least one SDoH variable with age, race and ethnicity, and sex included most often. Future studies to inform the role of SDoH data in translational research and science are recommended, and a draft SDoH data checklist is provided.

Museum engagement may be an effective approach for decreasing social disconnection and pain among individuals living with chronic pain. In October 2019, we launched a randomized controlled trial to assess the feasibility of museum engagement for individuals living with chronic pain; the study was halted in March, 2020 due to Covid-19-related safety concerns. This paper describes the process of transitioning from in-person to virtual museum programing in order to continue the study. Virtual museum programing is a feasible option for individuals living with chronic pain that is amenable to research and which may improve accessibility, inclusivity, and scalability relative to in-person programing.

In the spring of 2020, New York City was at the epicenter of the COVID-19 pandemic in the USA, resulting in disruption of TL1 and KL2-mentored Clinical and Translational Science (CTS) research at the Icahn School of Medicine at Mount Sinai (ISMMS). The impact of the pandemic on trainees’ research productivity and career plans was explored using a qualitative survey. Participant responses were analyzed using coding and categorization. Six key themes emerged: redirection of effort, reduced access to people, lack of access to resources, home as a workplace, future uncertainty, and stress and anxiety. Insight into participant experiences allows for the development of support strategies and resources to address trainee needs.