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Alpha frequency tACS and pain avoidance learning in chronic pain patients

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NCCIH - National Center for Complementary and Integrative Health

PROJECT SUMMARY/ABSTRACT The overarching goal of this project is to gain mechanistic insights into the brain-behavior relationship underlying pain avoidance and its modulation using alpha-frequency transcranial alternating current stimulation (tACS) targeting the dorsomedial prefrontal cortex (dmPFC). While adaptive avoidance of pain aids in survival, maladaptive pain avoidance plays a key role in the development and maintenance of chronic pain hampering physical therapy and rehabilitation, especially in conditions like complex regional pain syndrome (CRPS) with a high burden of psychopathology. An emerging perspective characterizes chronic pain as a learning impairment - an inability to differentiate between situations predicting threat vs. safety - resulting in fear and avoidance spreading to potentially safe activities. Although much of the impairment is attributed to the dysfunction and disinhibition involving the prefrontal networks, the underlying neurophysiology and its causal relationship with pain avoidance behavior is yet to be determined. We take a multimodal approach to study how behavior, brain neurophysiology and autonomic nervous system (ANS) responses are modulated by enhancing the alpha oscillatory power in the dmPFC. Given the alpha oscillations in the dmPFC facilitate inhibitory processes required for decision making and learning, we hypothesize that enhancing alpha power via tACS will promote adaptive pain avoidance behavior in CRPS patients. In Aim 1 will use an instrumental pain avoidance task in conjunction with a computational reinforcement learning model to quantify the effects of tACS on threat and safety learning behaviors. The task will be performed while we collect magnetoencephalography (MEG), a state-of-the-art brain imaging device. Aim 2 will examine both pain avoidance task-related and resting-state MEG activity to quantify the effects of tACS on brain neurophysiology in terms of alpha oscillatory power and connectivity. Aim 3 will evaluate the effects of tACS on ANS responses in terms of heart rate variability – a parasympathetic measure from EKG – and fear arousal – a sympathetic measure from galvanic skin conductance responses. The data from this project will clarify the spectral specificity with which pain avoidance behavior is represented in the dmPFC and ability to directly modulate them. This project is the first of its kind to investigate affective- motivational dimensions of chronic pain using tACS and will establish the foundation for future augmented protocols combining tACS with rehabilitation.

Up to $408K
2028-07-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

An implementation science approach to integrating long-acting injectable treatments for HIV and opioid use disorder in the context of Medicaid expansion

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NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Candidate. The objective of this proposed K01 award is to provide Dr. Nicole Kelly with the mentored training and research experience necessary to become an independent investigator who bridges implementation science and non-partisan policy evaluation to close gaps in access to novel effective treatments for HIV and substance use disorders. Dr. Kelly is a Postdoctoral Fellow in the Division of Infectious Diseases and Global Public Health at the University of California San Diego. This award will support her transition to independence by: 1) building substantive expertise in novel effective treatments for HIV and opioid use disorder (OUD), 2) developing expertise in dissemination and implementation science frameworks, strategies, and trials, 3) obtaining advanced training in quasi-experimental methods to evaluate the real-world impacts of policies on the HIV epidemic, 4) strengthening professional development skills to support a successful career as an independent NIH-funded HIV and substance use researcher, and 5) gaining additional training in the responsible conduct of research among people with HIV and OUD (PHIVOUD). She will accomplish these training aims through a structured program of didactic courses, workshops, conferences, directed readings, meetings with mentors, and hands-on experience. Research and Environment. Long-acting injectable (LAI) treatments for HIV and OUD are highly effective biomedical tools that can reduce medication burden, increase adherence, and promote HIV viral suppression. However, use of LAI anti-retroviral therapy and medications for OUD (LAI-ART and LAI-MOUD) remains low in the United States, possibly due to fragmented health policy and clinical systems. Expanding Medicaid in all states and integrating LAI-ART and LAI-MOUD delivery so that patients receive injections at the same visit could be policy- and clinic-level interventions to increase LAI access. The proposed research will provide Dr. Kelly with the training to address these research questions and the clinical collaborations needed to transition to independence. She will use North Carolina (NC) as an example of a state that recently expanded Medicaid to evaluate the impact of Medicaid expansion on LAI-ART/MOUD use among PHIVOUD using quasi-experimental methods (AIM 1). She will then use mixed methods to quantitatively define policy implementation gaps in LAI use by evaluating who is and is not accessing LAIs in NC pre- and post-Medicaid expansion, and qualitatively assess implementation needs to integrate LAI delivery in a state with (NC) and without [Florida (FL)] Medicaid expansion (AIM 2). Finally, she will integrate AIM 1-2 findings to develop and assess implementation blueprints with actionable guidance for integrating LAIs in NC and FL (AIM 3). This training will position Dr. Kelly as the only investigator with the expertise to accelerate the implementation of novel HIV and substance use treatments across distinct policy settings in the Department of Medicine at the University of California San Diego.

Up to $200K
2031-07-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Analysis of the local and global responses in the placenta syncytiotrophoblast

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NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

ABSTRACT The multinucleated syncytiotrophoblast (STB) is a tissue-sized single cell that separates the maternal and fetal vasculature during pregnancy. The STB wraps around the villous trees of the placenta lobules, encasing them in a cell with billions of nuclei in a common cytoplasm. This giant single cell facilitates the exchange of nutrients, is essential for fetal immunoprotection, is the primary producer of pregnancy hormones, and performs critical metabolic roles. Further, the STB must simultaneously respond to gradients in oxygen, nutrients, maternal hormones, and pathogens that fluctuate in space and time. How does a single cell support these diverse homeostatic tasks and simultaneously respond to local stresses? We hypothesize that the multinucleate organization is fundamental to supporting the many demands of production, metabolism, and stress response required of a single STB cell. Recent work and our preliminary data show that individual nuclei within the STB indeed have distinct transcriptional programs despite all sharing the same cell cytoplasm. This indicates that STB nuclei are heterogeneous in activity and function. Notably, GO terms for each of the STB nuclear clusters show mutually exclusive expression of homeostatic STB functions or stress response genes. Therefore, nuclear individuality could both facilitate the myriad of STB functions and the insulation of the stress response by spatially clustering in different regions depending on local functions or conditions. Major gaps in knowledge include how different nuclear identities are spatially patterned in the tissue, how nuclear identities arise mechanistically, and the functional consequences of nuclear heterogeneity within the STB cell. Spatial organization of the STB is disrupted in multiple forms of preeclampsia, a pregnancy disease that stems from improper placentation in the first trimester or maternal inflammation. We predict that the systemic stress seen in preeclampsia perturbs the functional balance and spatial organization of homeostatic and stress response pathways in STB nuclei. The proposed experiments will analyze heterogeneous gene expression in healthy and preeclamptic placentas with the following aims: Aim 1: Dissect the spatial patterns of RNA expression and localization in the STB cell and Aim 2: Identify the function and mechanism of heterogeneous nuclear gene expression in the STB. We will apply state-of-the-art spatial transcriptomics on placentas from healthy and preeclamptic pregnancies to analyze gene expression patterning in different locations of the STB. Using super-resolution, live-cell imaging, and genetic manipulations of placenta organoids, we will determine the mechanisms generating specialized nuclear transcription and the functional consequences of heterogeneous nuclear gene expression. This work will establish a functional atlas of STB nuclear identity patterning in health and preeclampsia and act as a guide to discover molecular drivers of pregnancy disease.

Up to $694K
2031-03-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Annual Program Statement for Public Diplomacy Programs (Public Diplomacy Grants Program)

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U.S. Mission to Tajikistan

Purpose of Public Diplomacy Grants: PDS Embassy Dushanbe invites proposals for programs that strengthen ties between the United States and Tajikistan in priority program areas (see below) in order to highlight shared values and promote bilateral cooperation. All proposed programs must include an American element, either through a connection with American expert/s, organization/s, or institutions/s, usage of American educational/informational resources, or any other activities that promote or contribute to increased mutual understanding between the people of the United States and people of Tajikistan. Competitive proposals will promote continued and sustainable cooperation between the people of the United States and Tajikistan even after the project concludes. Competitive proposals will include partnership with Tajik governmental bodies, and to organizations that have a demonstrated track record of implementing such programs. Examples of programs could include, but are not limited to: Academic or professional exchanges, lectures, seminars, trainings, speaker programs, or workshops; and Artistic, cultural, or sports workshops, masterclasses, joint performances, and/or exhibitions. PDS welcomes proposals that support one of the following priority program areas: TOPIC 1: Counter Gender-based Violence (GBV) Domestic violence (DV) and gender-based violence (GBV) remains a serious issue in Tajikistan and much of the world. In a USAID-funded survey in Tajikistan, 97% of men and 60% of women believed spousal abuse was justified. Cases of GBV and DV are underreported because victims wish to avoid humiliation, reprisal, or social stigmatization, or believe it may have been warranted. Further, authorities wishing to promote traditional gender roles frequently dismiss domestic violence as a family matter or only gave a warning or fine. Government resources for survivors are also limited. Project Audience(s) may include: Religiously or socially conservative communities, especially Tajik men (18-50 years old) High school students (14-18 years old.) Youth and emerging leaders (18-35 years old.) University teachers and students. Labor migrants and spouses of labor migrants. Tajik advocacy groups. Government bodies. Independent media including bloggers and vloggers Countering Gender-Based Violence Project Goal: Empower civil society and communities in Tajikistan to prevent and prosecute cases of Domestic Violence (DV) or Gender-Based Violence (GBV) through community-led initiatives. Project Objectives (may address one or more of the following): Messaging campaigns or awareness raising activities, such as sports diplomacy, should engage and target both men and women. Having men as the face of campaigns, or having men speak to men standing against GBV, demonstrates solidarity and emphasizes that eradicating gender-based violence is the collective responsibility of everyone, regardless of gender. Improve collaboration between civil society, independent media, and the government to identify and address gaps in existing laws and policies that criminalize GBV/DV, provide protections for victims, and establish legal frameworks for persecution. Raise awareness among vulnerable populations about laws, rights, and support services concerning early marriage, domestic abuse, harassment, divorce, alimony, and other civil rights. TOPIC 2: Promoting Women s Economic Empowerment and Entrepreneurship Due to the high rate of male labor migration and unemployment, more Tajik women are exploring ways to financially support their households and communities. However, women entrepreneurs' activities are highly dependent on the effectiveness of the business environment in the country. Moreover, the mountainous regions throughout the country challenge the development of entrepreneurship, as does lack of information, limited access to financing for starting a business, and other socio-economic conditions. Nevertheless, successful small business development creates new employment opportunities in Tajikistan and helps women support themselves and their families. Small businesses are fast becoming the main source of income for women in Tajikistan. Proposed projects should enhance women s participation, promotion, and longevity in the Tajik economy and ability to assume leadership positions. Projects should clearly support the protection of economic rights for women and increase respect for women s rights in society to improve their independence and proactive role in Tajik society. Project Audience(s) may include: Women from rural areas (including the spouses of labor migrants) and women entrepreneurs. Small businesses in rural areas. Business associations. Financial and government institutions. Tourism agencies (including guesthouse and small hotels). Community leaders and youth demonstrating leadership potential in these areas. Women s Economic Empowerment Project Goal: Increase the capacity of women from underserved, rural communities, including the spouses of labor migrants, to participate or increase their participation in the Tajik economy. Improve women's economic opportunities in Tajikistan by increasing the capacity of women to start, establish, or expand their own companies. Project Objectives (may address one or more of the following): Develop the business and technical skills of women in rural communities to increase employability, launch and/or improve their own businesses. Establish and conduct activities with a professional network for women from under-represented communities, including the spouses of labor migrants, to support mentorship relationships and collaborative initiatives among network members that go beyond the conclusion of project activities. o Projects could connect women s entrepreneurship in the development of tourism around newly recognized UNESCO heritage sites. o Increase awareness of tourism initiatives and employment opportunities centered around newly designated UNESCO heritage sites. o Projects could seek to increase participation of women from underserved and target communities in the fields of Science, Technology, Engineering, and Mathematics (STEM). Increase women s knowledge and understanding about their legal rights in society and how to advocate for the respect of those rights. o Increase women s knowledge and understanding about their legal rights in the workplace, including rights related to employment, equal pay, job security, and access to economic opportunities. o Equip Tajik women with the ability to advocate for the recognition and enforcement of these rights. Promote women s economic empowerment and entrepreneurship through support from start-up hubs, corporate social responsibility, and/or access to finance. Emphasis should be placed on strengthening chambers of commerce, entrepreneurs, and core private sector industries through interactions or linkages with U.S. counterparts. o Facilitate access to funding resources and financing opportunities for women entrepreneurs to launch and grow their businesses. o Strengthen organizational capacities of chambers of commerce to support business development of aspiring female entrepreneurs. o Facilitate interactions and linkages between women entrepreneurs, chambers of commerce, startup hubs, and private sector industries in Tajikistan and their U.S. counterparts. TOPIC 3: Sharing America with Tajikistan The United States values innovation, creativity, critical thinking, freedom of expression, democratic principles, economic growth, and security. The United States supports a sovereign and independent Tajikistan, which includes support for a well-informed, discerning public who can inoculate itself against disinformation. Both the United States and Tajikistan have rich cultural traditions as shown in literature and storytelling, theater and performing arts, film, music, dance, sport, and education. Educational, cultural, and other exchange activities are a great way to engage the public, especially at-risk youth and those with neutral views or misconceptions about the United States, in order to bridge our cultures, deepen understanding, and discuss topics of mutual importance. Proposed projects should strengthen understanding between the United States and Tajikistan and advance areas of mutual interest by leveraging the experiences and lessons learned from the United States, while respecting cultural differences. Project Audience(s) may include: Tajik audiences who have not had exposure to the United States before. Youth 16-35. Academia, professors, and teachers. Civil society, non-government organizations, and associations/organizations promoting shared values or areas of mutual interest. Information professionals (media outlets, managers, editors, journalists, influencers). Religious and community leaders. Entrepreneurs and business community advocacy organizations. National and subnational government officials. Project Goal: To share American values, such as freedom of expression, respect for human rights, and celebrate/promote respect for diversity and social inclusion, while also improving access to objective information and increase media literacy and critical thinking skills to analyze mis and disinformation aimed at the United States. Project Objectives (may address one or more of the following): Raise awareness about shared U.S.-Tajik values and partnerships through trainings, workshops, masterclasses, joint performances, or other projects by U.S. and/or Tajik experts. Increase access to American content by Tajik audiences (such as book translations) that promote U.S. democratic and rights-based values. Increase collaboration between local, state, and civil society actors/stakeholders on well-defined social issues affecting both the United States and Tajikistan by sharing U.S. models of government-community engagement, or by working with U.S. experts/peers. Increase the effectiveness of individuals, organizations, and coalitions working to advance and/or advocate for respect and the promotion of human rights. Strengthen the ability of Tajik media professionals to develop accurate and fact-based informational media campaigns through digital skills building and training initiatives based on U.S.-best practices. Increase production and publication of objective, fact-based and editorially diverse media content by Tajik media professionals. Increase critical thinking skills, especially for youth and publics with a neutral or view or misconceptions about the United States, to identify and critically analyze sources of misinformation and disinformation. In addition to the specific requirements listed above by program area, all proposals must: 1. Clearly indicate the primary activity area to which it is being submitted for consideration. 2. Focus on the key public diplomacy audiences and activities specified in the areas, provide programs for underserved geographic regions of Tajikistan, as well as non-elite schools (if applicable); 3. Clearly delineate how elements of their program will have a multiplier effect and be sustainable beyond the life of the grant; 4. Provide a traditional and/or social media plan for marketing program activities and outcome, if applicable 5. Identify the cities/districts in which activities will take place. 6. Identify specific outcomes to be achieved by the end of the grant period. 7. Identify any tools (surveys, beneficiary interviews, focus groups, etc.) that will be developed for Monitoring and Evaluation purposes. Applicants must also demonstrate competency to manage all financial aspects of the project, including participant costs and transparent arrangements of sub-grant relationships with partner organizations, if applicable.

$5K – $45K
rolling
other

Free to search & build · $99 one-time to unlock the application pack · No subscription

Antibiotic-attributable arsenicosis risk: toxicity and carcinogenesis

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NIEHS - National Institute of Environmental Health Sciences

Abstract Arsenic is a global environmental toxin and known human carcinogen that contaminates the drinking water of over 200 million people. Despite accounting for host factors such as genetics and diet, there is significant inter- individual variability among similarly exposed individuals in the development and progression of arsenic-related diseases (arsenicosis), including bladder cancer, diabetes, and cardiovascular disease. Emerging evidence implicates the gut microbiome as a key modulator of arsenic toxicity. Notably, evaluation of murine models of human arsenicosis has demonstrated that antibiotic-induced gut microbiome disruption significantly increases arsenic toxicity and recapitulates interindividual susceptibility seen in humans. These findings are concerning because every year ~70% of Americans receive antibiotics that could trigger or exacerbate the long-term health consequences of arsenic. Antibiotic use and microbiome diversity are not part of current risk assessments of arsenic or other environmental toxicants. This project tests the overarching hypothesis that antibiotic-induced disruption of the gut microbiome increases arsenic toxicity and carcinogenesis in vivo. In Aim 1, a humanized mouse model will be used to evaluate how commonly prescribed antibiotics in the US influence arsenic toxicity, using a standardized morbidity scoring system, microbiome sequencing, arsenic speciation analysis, and tissue histopathology. In Aim 2, carcinogenesis of the bladder epithelium will be compared in different groups of microbiome competent and antibiotic-treated mice using an established co-exposure model that combines arsenic with the bladder-specific carcinogen, BBN. These studies will rank antibiotics by their toxicity and carcinogenic potential in the context of arsenic exposure and help define microbiome-targeted strategies to reduce disease risk. A fellowship training plan has been developed around this research that provides a comprehensive, interdisciplinary instruction in toxicology, oncology, microbiome research, and data analysis under the mentorship of experts in these fields. Training goals will be achieved in a highly collaborative and supportive environment with access to state-of-the-art facilities for gnotobiotics, pathology, and microbiome analysis. Completion of this project will enhance the candidate’s understanding of microbiome–toxin interactions in preparation for a successful, independent research career, and holds great potential to significantly improve risk assessment for arsenic and other environmental carcinogens.

Up to $36K
2028-05-27
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Applying novel imaging and transcriptomics to mechanisms of cirrhosis- related kidney dysfunction

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Cirrhosis, the late-stage complication of liver disease, stands as a leading cause of death globally and frequently causes kidney dysfunction. Yet, the mechanisms leading to kidney function loss in cirrhosis remain incompletely understood, which in turn limits the development of effective therapeutic options. I have generated data showing subclinical injury to the proximal kidney tubules (PTs) in stable outpatients with cirrhosis irrespective of glomerular filtration rate (GFR), the prevailing clinical assessment of kidney function, suggesting PTs are an early target in cirrhosis that may not be captured by glomerular markers. Contrasting with passive filtration, the tubules depend on kidney cellular energy production for solute secretion and reabsorption. Various pathways have linked cirrhosis to impaired tubular metabolism including mismatched demands for sodium/water reabsorption, exposure to retained bile acids and toxins, and pro-inflammatory gut bacterial products, however further investigation of these early mechanisms is challenged by a lack of measures aligned with the target of injury or studies in patients with cirrhosis already experiencing overt kidney disease. I hypothesize that the collective ischemic and toxic-metabolic environment causes attenuation in kidney cellular metabolism, affecting downstream energy-dependent functions of tubular secretory clearance (TSC) and reabsorption, that is not captured by glomerular markers alone. I propose a prospective nested cohort study of patients with cirrhosis characterized with longitudinal data and biosample collections, multi- modal imaging, and gene expression profiling, to reveal novel pathways of kidney dysfunction and potential therapeutic targets, as well as more holistic assessments of kidney function beyond GFR. I will recruit 140 patients with cirrhosis and preserved eGFR to participate in 3 study visits to determine the association of baseline measures of PT function and injury with kidney-related outcomes (eGFR slope, acute kidney injury [AKI], and ascites severity). I will apply novel methods developed in our lab to estimate TSC by measuring plasma and urine levels of highly secreted endogenous solutes, which I have used in studies of AKI, drug clearance models, and CKD development. In a sub-cohort (N=20) compared to age-matched controls (N=20), I will delineate the effect of cirrhosis on tubular oxidative metabolism using state-of-the-art imaging with 11C- acetate as well as measuring TSC using an exogenous tracer, 99mTc-MAG3. Finally, I will obtain kidney biopsies in a sub-cohort (N=9) of patients with cirrhosis to characterize tubular pathways of injury, metabolism, and fibrosis using a novel spatial transcriptomics platform. As part of this career development award, this work will allow me to develop new expertise in study design, systems biology, and biostatistics, yield a novel cohort and data in patients with cirrhosis to uncover new insights into mechanisms of kidney dysfunction, and provides a basis for future discovery to develop monitoring and treatment strategies as an independent translational researcher of kidney dysfunction in cirrhosis.

Up to $193K
2030-11-30
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

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