The Indiana Clinical and Translational Sciences Institute recently announced recipients of its 2016-17 Global Health Research Pilot Projects and Pilot Funding for Research Use of Core Facilities awards. This period, the Indiana CTSI granted funding awards to 27 investigators from Indiana University, Purdue University and the University of Notre Dame.
The global health research pilot grants, a collaboration of the Indiana CTSI and IU Center for Global Health, encourage the development of innovative, interdisciplinary research that seeks to address key global health challenges and improve health outcomes in resource-limited settings.
The core facilities pilot funding program is intended to promote the use of technologies and expertise afforded by Indiana CTSI-designated cores available at all partner institutions.
The 2016-17 Global Health awardees are:
- Suzanne Babich, Richard M. Fairbanks School of Public Health, IUPUI, will assess global health leadership training needs in Kenya and Nigeria. Babich and her team’s research will support the growth of a multi-country network of innovative and translational doctoral programs throughout sub-Saharan Africa aimed at creating effective and sustainable solutions to the continent’s most complex public health issues. It will also accelerate the establishment of the first doctoral program in global health leadership in east Africa, as well as a center of excellence in implementation research.
- Kenneth Cornetta, IU School of Medicine, will study telecommunication as a means of delivering home hospice care to patients at the end of their lives. Cornetta and his team hypothesize that telecommunication will provide a way for low- to middle-income countries to provide this essential part of comprehensive cancer care for patients and their families.
- Leslie Anne Enane, IU School of Medicine, will investigate critical gaps in care and potential interventions for hospitalized adolescents with HIV infection at Moi Teaching and Referral hospital in Eldoret, Kenya. This qualitative research project aims to study factors that contribute to significant hospitalization and mortality in this population.
- John Humphrey, IU School of Medicine, will use a phylogenetics approach to address the uncertain impact of vertical and horizontal transmission among adolescents living in HIV-affected families. The study seeks to enhance understanding of epidemiologic drivers of HIV infections and inform the implementation of prevention and treatment strategies.
- Connie H. Keung, IU School of Medicine, will study the epidemiology of trauma and trauma-related resources at a National Referral Hospital in western Kenya. The research project aims to assess the resources and equipment available for trauma care and implement a web-based database to measure the prevalence of various trauma-related injuries among patients at Moi Teaching and Referral Hospital in Eldoret, Kenya.
- Sonak Pastakia, College of Pharmacy, Purdue University, will evaluate locally sourced compression therapy for the treatment of chronic venous leg ulcers and management of Kaposi sarcoma leg lymphedema in western Kenya. The research could have far-reaching implications for the treatment of these prevalent conditions across East African and sub-Saharan Africa.
The Pilot Funding for Research Use of Core Facilities awardees are:
- Uma Aryal, Purdue Proteomics Facility, Purdue University
Proposal title: “Proteomic analysis of protein complex composition and dynamics in type 2 diabetes”
Proposal abstract: Type 2 diabetes may affect 35 percent of the U.S. population by 2050, and is characterized by insulin resistance in skeletal muscle and adipose tissue. Decades of research into mechanisms of insulin resistance have mostly focused in insulin signal transduction and mitochondrial and cytosolic pathways. However, little is known about how insulin resistance induces changes in protein oligomerization. Knowledge about protein complex dynamics can provide greater understanding of the cellar pathways of type 2 diabetes, help to identify new drug targets, and develop new and more efficient drugs. Therefore, the proposed research is highly relevant to biomedical and translational research. - Angela Bruzzaniti, IU School of Dentistry, IUPUI
Proposal title: “Mechanism of action of bone marrow niche cells, osteomacs and osteoblasts”
Proposal abstract: The hematopoietic niche consists of multiple cell types that function in concert to sustain the hematopoietic stem cell (HSC). Megakaryocytes (MK) are hematopoietic cells that are responsible for the production of platelets. Several studies demonstrate that MKs promote the proliferation of osteoblast (OB) as well as osteomacs (OM, bone resident macrophages) and that removal of OB or OM significantly decreases the proliferation of the other cell type, indicating that MK may regulate HSC function by coordinating crosstalk between OBs and OMs. We will sort for OB and OM population and examine signaling via the MCSF/cfms pathway and identify key genes involved in the MK-mediated increase in OB and OM proliferation. Our long-term goal is to enhance the hematopoietic niche, improve bone marrow transplantation strategies and increase skeletal bone formation. - Kimberly Buhman, School of Health and Human Sciences, Purdue University
Proposal title: “Electron microscopy analysis of organelle interactions and morphology contributing to altered dietary fat absorption in mice resistant to diet-induced obesity”
Proposal abstract: Dietary fat absorption by the small intestine is essential for survival but can contribute to obesity and related metabolic diseases when fat is consumed in excess. Thus, increasing our understanding of the cellular and molecular regulation of this process is crucial for the development of novel therapeutic approaches to combat these health issues. Our objective is to develop new methodology for identifying interactions between organelles in mouse enterocytes using both transmission electron microscopy (TEM) and electron tomography (ET). In addition, we want to identify and quantify alterations in CLD and mitochondrial morphology in mice resistant (Dgat1-/-) versus susceptible (WT) to diet induced obesity (DIO). These methods will provide preliminary data about potential lipid channeling pathways that may be altered and worth investigating further in this DIO resistant model. Once these methods have been optimized, they can also be applied to other dietary and genetic models to visualize organelle interactions that contribute to the process of dietary fat absorption. - Lingling Chen, College of Arts and Sciences, IU Bloomington
Proposal title: “A chlamydial nuclear effector in host response to chlamydial infection”
Proposal abstract: Chlamydia trachomatis is an important human pathogen that causes infectious blindness and sexually transmitted infections, yet information on the molecular pathogenesis of chlamydial disease is limited, which has hindered development of vaccines and therapeutics. Chlamydial infection alters transcription of a massive number of host genes, including pathological ones, and chlamydial genes have been implicated in orchestrating the large-scale host cell transcriptional activity. Chlamydia secretes CT311 to the host cell nucleus, and we propose that CT311 functions as the nuclear effector to mediate host cell transcriptional including pathological response. In this pilot project, we test whether CT311 can affect host cell transcriptome using next-generation sequencing analysis, and whether it can interact with host cell proteins using mass spectrometry analysis. - Robert Graham Cooks, College of Science, Purdue University
Proposal title: “Accelerated biomarker discovery by MRM-profiling for Zika virus diagnosis in blood samples”
Proposal abstract: This project aims at applying a mass spectrometry-based accelerated biomarker discovery approach named MRM-profiling to detect the presence of Zika virus (ZIKV) infection in blood. This diagnostic approach is based on small molecule signatures which have been recently developed at Purdue University. MRM-profiling has been applied with satisfactory results to Parkinson’s disease, atopic dermatitis, and to diet compliance. The assay can be translated to a miniature mass spectrometer for point-of-care diagnosis for fast (minutes) and simple diagnosis (performed on site by a nurse or technician) with only a microliter of blood collected by finger pricking. This collaborative and multidisciplinary project led by Dr. Graham Cooks includes professors at the University of Sao Paulo working directly with patients infected by ZIKV. Support for handling and transporting samples will be provided by Dr. Richard Kuhn’s laboratory and the Purdue Institute of Inflammation, Immunology and Infectious Diseases. - Guoli Dai, School of Science, IUPUI
Proposal title: “Identification of Ascl1 target genes in maternal liver during pregnancy”
Proposal abstract: The project is to understand how a transcription factor named Ascl1 acts in regulating maternal liver adaptive responses to pregnancy. We will use RNA-Seq approach to reveal the gene network regulated by Ascl1 in maternal liver of pregnant mice. The data will allow us to gain insights into pregnancy-associated liver diseases. - Vincent Jo Davisson, College of Pharmacy, Purdue University
Proposal title: “Improving pharmacokinetics of Diphyllin V-ATPase inhibitors”
Proposal abstract: There is a significant unmet need for treatments of diseases caused by Ebola and Marburg viruses. Outbreaks of infections are a global threat. An early stage drug discovery project at Purdue University has identified a new class of antiviral agents that have potential for treating individuals infected with these viruses. The project team requests access to shared resources to generate preliminary in vivo pharmacokinetic data to support the project and enhance the potential for new sponsored research. - Carmella Evans-Molina, IU School of Medicine
Proposal title: “Assessment of β cell function in Darier-White and Hailey-Hailey Disease”
Proposal abstract: Mouse and in vitro models of SERCA2b and SPCA1 loss of function demonstrate alterations in pancreatic beta cell insulin production and secretion. Darier-White Disease (DWD) and Hailey-Hailey Disease (HHD) are rare autosomal disorders arising from haploinsufficiency of SERCA2 and SPCA1, respectively. Here, we will test whether humans with DWD and HHD exhibit similar alterations in insulin secretion in response to a hyperglycemic challenge. Data generated from this work will be used to support a new R01 application. - Shannon Hawkins, IU School of Medicine
Proposal title: “Novel integration of MiRNAs for discovery of pathways in endometrioid ovarian cancer”
Proposal abstract: The presence of endometriosis, a benign pathologic growth of endometrium outside the uterus, increases the risk of ovarian cancer up to 50 percent, making 5 million women in the U.S. at increased risk. Women with endometriosis are more likely to develop rare subtypes of epithelial ovarian cancer, including endometrioid and clear-cell cancer, but not the more common high-grade serous disease. Studies have shown that with tumors with concurrent endometriosis having improved prognosis. Therefore, a critical need exists to understand the genomic and pathophysiological differences between these subtypes to develop more focused, subtype-specific therapies. Our long-term goal is to understand the functional role of miRNAs in ovarian tumors with concurrent endometriosis to determine what makes them unique. Our central hypothesis is that the miRNA profiles are unique for tumors with concurrent endometriosis, leading to downstream effects on gene expression and improved outcomes in women. The overall objective of this Pilot Funding for Research Use of Core Facilities application is to discover pathways mediated by miRNAs in endometrioid ovarian cancer with concurrent endometriosis for future studies of subtype-specific therapy. - Kirsten Kloepfer, IU School of Medicine
Proposal title: “Early feeding choices are associated with the gastrointestinal microbiome and early episodes of wheeze”
Proposal abstract: With asthma prevalence rates increasing each decade, identifying factors that influence the development of asthma is critical. The project described in this application will gather important data about early milk choices and the influence of this choice on gut colonization, airway dysbiosis and ultimately airway changes. We will utilize samples from an existing cohort and the Center for Genomics and Bioinformatics to investigate these associations. - Sachiko Koyama, IU School of Medicine
Proposal title: “Trans-generational influence of pheromones in mice”
Proposal abstract: Using mice as model system, we found in our previous study that exposure to male pheromone stimulates the expansion of mammary glands in virgin females and the differences had a long-term impact, producing heavier mammary glands during the post-delivery lactation period if they were mated after exposure to the pheromone. Critically, the offspring of these pheromone-exposed females as well as the cross-fostered offspring of the control group females raised by these pheromone-exposed females showed higher cognitive function as adults (Koyama et al. 2015). We hypothesize that the exposure to male pheromone stimulated mammogenesis, producing long-term influences and affecting milk synthesis in a way that some key milk component(s) were secreted in the milk of these females resulting in beneficial “nutritional epigenetics” that affected brain development. In this study, we plan to conduct total RNA-seq of the brain of mouse pups raised by pheromone-exposed females and control group females at the Center of Genomics and Bioinformatics in order to determine the genes that are up/down regulated, and we expect that the results (1) will provide significant information for our on-going project on the nutritional epigenetics, (2) will push our project strongly forward in our future grant applications, and (3) produce a significant improvement in our knowledge of the role of milk composition in the growth of human babies. - Hui-Chen Lu, College of Arts and Sciences, IU Bloomington
Proposal title: “Preclinical studies of microRNAs in neurodegeneration”
Proposal abstract: Alzheimer’s Diseases (AD) is the most prevalent form of neurodegenerative disease and dementia. The ultimate goal of the proposed research is to identify microRNAs that are altered in early AD and explore their in-depth regulatory function as well as their feasibility as biomarkers to monitor pathological changes in living subjects and to design new therapeutic interventions. - David Nelson, IU School of Medicine
Proposal title: “Development of a diagnostic for an emerging urethrotropic clade of Neisseria meningitides” - Thomas O’Connell, IU School of Medicine
Proposal title: “Metabolic Analysis of Chemotherapy Induced Cachexia with Extracellular Flux Analysis”
Proposal abstract: Cancer cachexia is a devastating muscle-wasting syndrome that is observed in up to 80 percent of individuals with advanced cancer. The preferred treatment strategy for most cancers is chemotherapy, which, while attempting to reduce the tumor burden, can create an additional source of muscle wasting. Recent studies suggest that defective mitochondrial homeostasis and increased oxidative stress are critical mechanisms promoting chemotherapy-induced cachexia. Given the role of mitochondria as the energetic engines of the cell, we hypothesize that chemotherapy induced cachexia will result in profound alterations in cellular energetics. We propose to use the Seahorse Extracellular Flux platform on in vitro models of chemotherapy-induced cachexia to provide mechanistic insights into the altered energetic pathways. - Carlos Perez-Torres, College of Health and Human Sciences, Purdue University
Proposal title: “Cholesterol-induced modifications in the functionality of nanoparticles for MRI applications”
Proposal abstract: Nanoparticles are increasingly being utilized for biomedical applications such as magnetic resonance imaging. High cholesterol is a prevalent underlying disease condition within our population, which may alter the functionality of nanoparticles. This proposal will specifically investigate the influence a high cholesterol physiological environment on the relativity and biodistribution of magnetic nanoparticle compared to normal evaluated, healthy environments. This research proposal utilizes MRI, nanoparticles, relativity, biodistribution,and toxicity assessment. This proposal will also provide us with new knowledge regarding how a typical human condition of high cholesterol may influence a common diagnostic application while also establishing a foundation for future translational grant applications. - Kavita Shah, College of Science, Purdue University
Proposal title: “A bio-orthogonal high content chemical approach for rapid identification of the low abundance kinase substrates”
Proposal abstract: The goal of this proposal is to develop a bio-orthogonal high content chemical approach that enables rapid identification of the low abundance kinase substrates and their phosphorylation sites on a proteome-wide scale. We will specifically apply this methodology to identify the targets of LIMK2 kinase. - Cara Wellman, College of Arts and Sciences, IU Bloomington
Proposal title: “Do gonadal hormones mediate sex differences in microglial activation in prefrontal cortex?”
Proposal abstract: The effect of stress on medial prefrontal cortex (mPFC) is sex-dependent, yet very little is known about the mechanisms underlying this sex difference. We have recently found a sex difference in microglial activation state in male and female prefrontal cortex, and sex differences in the effect of stress on microglial activation. Microglia play a role in sexually dimorphic development, regulating synaptic plasticity, spine density, and injury-induced dendritic loss in unstressed males, and chronic stress-induced deficits in working memory and depression-like behaviors in males. Thus, differences in microglial activation could contribute to sex differences and differential stress effects in mPFC. This pilot experiment will use manipulations of gonadal steroids and assessment of gene expression in microglia isolated from mPFC to assess whether gonadal hormones mediate sex differences in microglial activation in mPFC. Addressing this issue will provide critical pilot data for an NIH R01 investigating the mechanisms by which microglia contribute to the differential responses to stress in mPFC. Given the sex differences in stress-related psychological disorders, the absence of information on the impact of stress on the prefrontal cortex of females, as well as the mechanisms underlying the observed sex differences, is problematic. Understanding the nature of sex differences in structures that are critical mediators of cognitive and emotional behavior, and the mechanisms that underlie them, may elucidate the neural bases of such disorders–a crucial first step in developing sex-specific interventions for stress-related disorders. - Clark Wells, IU School of Medicine
Proposal title: “The transcriptome of IDH1/P53 mutant progenitor astrocytes” - Yoon Yeo, College of Pharmacy, Purdue University
Proposal title: “Pharmacokinetics and biodistribution of carrier-free paclitaxel nanoparticles”
Proposal abstract: Nanoparticles are used to deliver anticancer drugs to solid tumors with leaky vasculature. However, clinical development of nanoparticles has been hampered by the limitations in physicochemical properties of nanoparticles, such as low drug loading efficiency and poor circulation stability. To overcome these challenges, we propose to develop a carrier-free nanoparticle formulation with high drug loading and circulation stability and have developed a new nanoparticle formulation system generally applicable to hydrophobic drugs. With the support of CTSI Pilot Funding, we will work with the Clinical Pharmacology Analytical Core (CPAC) and perform LC-MS analysis of blood and tissue samples of animals treated with the nanoparticles to confirm their advantage in pharmacokinetics and biodistribution as compared to a commercial drug Abraxane. - Zhong-Yin Zhang, College of Pharmacy, Purdue University
Proposal title: “Structural determination of full-length oncogenic phosphatase SHP2 by cryo-EM”
Proposal abstract: Chlamydia trachomatis is an important human pathogen that causes infectious blindness and sexually transmitted infections, yet information on the molecular pathogenesis of chlamydial disease is limited, which has hindered development of vaccines and therapeutics. Chlamydial infection alters transcription of a massive number of host genes, including pathological ones, and chlamydial genes have been implicated in orchestrating the large-scale host cell transcriptional activity. Chlamydia secretes CT311 to the host cell nucleus, and we propose that CT311 functions as the nuclear effector to mediate host cell transcriptional including pathological response. In this pilot project, we test whether CT311 can affect host cell transcriptome using next-generation sequencing analysis, and whether it can interact with host cell proteins using mass spectrometry analysis. - Siyuan Zhang, College of Science, University of Notre Dame
Proposal title: “Single cell transcriptome characterization of microglia during brain metastasis using Drop-seq”
Proposal abstract: Brain metastasis is the most devastating complication for cancer patients. Metastatic colonization – from single disseminated tumor cell to an overt metastasis tumor – represents a major bottleneck in the metastatic cascade. However, molecular mechanisms of how tumor cells adapt to the brain through dynamic cross-talk with the brain microenvironment cells are still largely unknown. Monocytes, particularly central nervous system-specific microglia, function as the primary guardian of the brain homeostasis. In response to neuroinflammatory diseases, microglia immediately activate and bone marrow-derived monocytes – largely excluded from the brain parenchyma during normal physiology – infiltrate brain tissue. Together, these two broad monocyte populations steer the course of neuroinflammation by non-redundant mechanisms. Therefore, it has been speculated that monocytes participate in the brain metastasis process. In our preliminary study, inhibiting monocyte function by genetic deletion of monocyte CX3CR1 receptor, a transmembrane glycoprotein receptor for monocyte chemotaxisis, significantly increased brain metastasis burden, suggesting an inhibitory role of infiltrating monocytes in brain metastasis. However, beyond this intriguing phenotypic observation, the precise molecular mechanisms of monocyte activation and infiltration dynamics in response to brain metastasis are still highly convoluted and technically unapproachable, largely due to the highly heterogeneous and dynamic nature of the monocyte ecosystem within the brain microenvironment.
