Lisa M. Guay-Woodford - US grants

Mutations that cause renal cystic disease provide powerful tools to identify the molecular determinants of renal cyst formation. In humans, genetic cystic kidney diseases are inherited as simple mendelian traits, exhibit wide variability in phenotype and account for approximately 10% of end stage renal disease in both adult and pediatric populations. Linkage studies that mutations in several distinct loci cause renal cystogenesis. yet, only some of the human loci have been mapped and to date none have cloned. The mouse provides an excellent experimental model to identify molecular determinants of renal cyst formation. In the mouse, several cystic kidney mutations have been described each disrupts a distinct gene and the mutant phenotypes closely resemble human diseases. Of these models, the congenital polycystic kidney (cpk) mutation is best characterized. Based on microdissection and cell biology data, we hypothesize that cpk is an important molecular determinant of both cystogenesis and the terminal differentiation of renal tubular epithelia. As the first step in a positional cloning strategy, my laboratory has mapped cpk to proximal mouse Chromosome 12. Of note, no recombination events were detected between cpk and D12Nyu2. Our genetic map: centromere-(Odc,D12Mit10)-(cpk,D12Nyu2)-(Tpo,D12Mit 12)-telomere, positions cpk within a 1.3 cM region centered on D12Nyu2. Based on this map, we will establish the molecular framework required to clone the cpk gene. The goals of this proposal are to: 1) construct a physical map of the chromosomal region centered on cpk using the techniques of pulsed field gel electrophoresis (PFGE) and yeast artificial chromosome (YAC) cloning; 2) identify candidate cpk cDNAs using the complementary strategies of HTF island identification, YAC- based cDNA selection and mRNA differential display and 3) characterize the candidate cpk cDNAs. Once the cpk gene is cloned, future studies will be directed at 1) functionally characterizing the molecular defect in this well-defined mouse model of PKD; and 2) determining the relationship between renal tubular cyst formation and renal tubular differentiation. In light of the extensive genetic conservation between mice and humans, we will also use the cpk gene to identify its human homolog and determine the role of this human gene in renal cystic disease.

A major focus in polycystic kidney disease (PKD) research is to identify genes involved in renal cyst development. Despite recent successes in cloning several human PKD genes, their roles in disease pathogenesis remain undefined. In addition, it appears that genetic background influences the expression of many PKD disease-susceptibility genes. The characterization of these putative modifying genes will be quite difficult in the complex, randomly mating, human population. As an alternative, mouse PKD mutations and their genetic modifiers may provide powerful resources to study genes and gene interactions involved in renal cystogenesis. Among the several mouse models in which PKD segregates as a single Mendelian trait, three mutations, cpk, bpk, and Tg737Rpw, closely resemble human autosomal recessive polycystic kidney disease (ARPKD). In these three mouse models as well as human ARPKD, renal cyst formation begins in utero and genetic background influences disease expression. Therefore, we hypothesize that these mammalian genes and their modifiers define a molecular pathway that is important in both renal cyst development and renal tubular differentiation. In this proposal, we will identify and characterize genes that influence the expression of the cpk mutation. Specifically, we will identify genes that accelerate the-development of renal cystic disease and cause bile duct plate abnormalities in the F2 affected progeny of an intersubspecific intercross between C57BL/6J-cpk/+ and Mus mus castaneus. In addition, we will map the bpk mutation, a second mouse model of human ARPKD. Then in a directed fashion, we will test whether the cpk genetic modifiers influence the phenotypic expression of the bpk mutation. Finally, we will construct congenic strains which isolate individual modifying loci in specific genetic backgrounds as the prelude to identifying and characterizing these genes. Therefore, this project will establish the molecular framework for identifying gene(s) that modify the disease pathogenesis in mouse recessive PKD. Our ultimate goal Is to use these genetic tools to dissect the molecular pathogenesis of human ARPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in the United States, affecting 1 in 400 to 1 in 1,000 individuals. The clinical and genetic factors associated with disease progression have been well-defined in the Caucasian population but there is a paucity of data for other racial groups, including African- Americans (AA). There is anecdotal evidence which suggests that glucose-6- phosphate dehydrogenase (G6PD) deficiency and sickle cell trait (SCT) are negative prognostic factors in AA ADPKD patients. At least three independent loci cause ADPKD in Caucasian populations. The genetic defect(s) in the AA population has not been established nor has the frequency distribution of these ADPKD loci. This project will characterize the natural history of ADPKD in the AA population of Alabama to determine whether specific clinical and genetic factors are associated with progression of renal disease. We will define the frequency of dichotomous variables previously associated with progressive renal dysfunction in Caucasians (including gender, hypertension, hematuria, nephrolithiasis, proteinuria, cyst rupture, and UTI) in AA ADPKD patients. Frequency of these variables will be compared in age-matched AA individuals with and without ESRD and correlated with age of onset of ESRD. Also, the frequency of SCT and G6PD deficiency in AA ADPKD patients will be determied and compared with the local AA population. These conditions will be correlated with their co-segregation with renal disease progression using chi-squared analysis. Finally, we will determine the DAPKD disease gene frequency in our AA cohort by performing genetic linkage analysis within each cohort. Knowledge of the gene distribution in AA ADPKD patients and putative co- morbid genetic risk factors will provide a better understanding of the molecular basis of this disorder and will be clinically useful in risk stratification and genetic counseling. This proposal is designed as a pilot study. We anticipate these studies can be extended to compare ADPKD in Alabama Caucasians versus AA. In addition, several PKD investigators have expressed interest in formulating a multi-center study to evaluate the national experience with ADPKD in AA patients.

DESCRIPTION (Adapted from the investigator's Abstract): Emerging evidence indicates that renal cystic disease in both humans and mouse models involves a multigenic pathway in which the disease-susceptibility genes act by cellular recessive mechanisms. These genes also appear to play critical roles in renal differentiation and maturation. The cpk mouse was the first polycystic kidney disease (PKD) model to be described and as such, it has been the most extensively characterized. While these studies have significantly contributed to our understanding of renal cystic disease, they have been conducted primarily in mice with advanced renal cystic disease. Therefore, the critical relationship between the normal epithelial differentiation and the initial events of renal cyst formation remains to be elucidated and the molecular basis for the cpk phenotype is as yet unknown. The ultimate goals of the PI are (1) to characterize the role of the cpk gene product in renal development by determining the molecular pathways in which it functions, and (2) to elucidate how the loss of function of this gene causes renal cyst formation. In this grant application, the PI proposes to establish the biologic and molecular framework for these investigations. The proposal is divided into two complementary projects. First, in Aim 1, they propose to test whether the prevailing hypotheses regarding renal cystogenesis apply to the genetically-defined, fetal cpk model that they have recently characterized. Second, they propose to clone the cpk gene. Aim 2 deals with the construction of a complete transcript map of the critical cpk interval. Aim 3 deals with the identification of the cpk gene from the transcript map generated. In Aim 4 they propose to examine the temporal and spatial expression of the cpk gene during the stages of renal organogenesis, e.g. induction, acquisition of stem cell character, fate determination, condensation, epitheliogenesis, polarization, and maturation. Significance: The cpk mutation represents one of a number of recessive +____________ mutations causing PKD in the mouse. Like most other spontaneous mutations, the severe kidney disease of this mutant demonstrates the importance of the normal cpk counterpart in renal function. Given that the mechanism of cystogenesis is not well understood, despite the information provided by the cloning of PKD1 and PKD2. There is an increased need for discovering new genes in mouse whose deregulation leads to renal cystogenesis. The preliminary work from the laboratories of the principal investigator and the collaborators has resulted in the placement of the cpk mutation to a region between D12Mit218 and D12Mit105 of mouse Chr 12. Based on recombination frequency the two flanking markers were placed 0.26 cM apart (approximately 5 X 10 exp 5 bp). The physical map of the cpk critical region is being generated. Based on the fine mapping data the human cpk homologue maps to Chr 2p24-2p25. The physical map is being generated. Approach: Specific Aim 1: Examine the prevailing hypotheses regarding renal +________ cystogenesis in fetal cpk mouse model. a) disruption in basement membrane 1 PATHOLOGY A SS 3 R01 DK55534-01A1 June, 1999 Guay-Woodford, Lisa M formation. b) dysregulation of cell proliferation and apoptosis. c) aberrant expression of the epidermal growth factor receptor (EGFR), polycystin, and polycystin-2. The hypothesis is that the loss of function of the cpk gene interrupts the terminal phases of renal tubulo-epithelial differentiation. They speculate that the proximate event in renal cystogenesis may be a dysregulation of basement membrane composition with subsequent dysregulation of cell-matrix interactions, cell proliferation, and apoptosis that occur in a hierarchical order. In order to test this they plan to examine the expression of entactin-1, laminin gamma1, polycystin-1, polycystin-2 and EGF-R in E15 control (+/+) and cpk/cpk kidneys. They also propose to analyze the cell proliferation and apoptosis in the same. The E15 kidney was chosen since light microscopy revealed tubular dilation only in pups homozygous for B6 alleles. This experiment will provide answers with respect to the altered events in the E15 diseased kidney due to the loss of the cpk gene. However, in order to either confirm or refute the hierarchical order speculated it may be important to study the developmental profile of all the factors proposed during cystogenic process (Time points earlier and later than E15 have to be considered). Specific Aim 2: Isolate all expressed sequences from the cpk candidate interval and construct a complete transcript map of the interval. Based on the Whitehead/MIT database a YAC contig that spanned the 0.26cM interval was generated. Presently they have almost generated a BAC contig of this region. Unfortunately the interval is rather large (750kb). The chance of cutting down this interval considerably is rather remote. Since, only two recombination events in this interval were noted previously and the supplemental data suggests that the SP6 end of BAC-358F10 does not cross the distal recombination event in BC65. In light of their latest results, the identification of additional polymorphic markers to further refine the recombination breakpoints of the cpk interval can take a backseat. The identification of all the expressed sequences from the cpk interval must take priority. As the PI has pointed out Exon trapping, Hybrid cDNA selection and EST database analysis are the ways to go. The use of shot-gun sequencing is not an economical approach especially with a region as big as 750kb (requiring 8,000-12,000 sequencing). Specific Aim 3: Analyze candidate transcripts and identify the cpk gene. The methods proposed by the investigator to analyze the coding part of the candidate genes isolated are logical and well thought out. However, no methods have been discussed to detect mutations in the promoter or intronic region. The in vitro functional complementation assay proposed to test the candidate cpk +__ _____ gene is not established at this juncture. Specific Aim 4: Characterize the temporal and spatial expression of the cpk gene in the mouse fetal kidney. The experiments designed to analyze the expression of the cpk gene in mouse fetal kidney are described well. Innovation: The project does employ a number of new methods and approaches. +___________ 1 PATHOLOGY A SS 4 R01 DK55534-01A1 June, 1999 Guay-Woodford, Lisa M However the project does not challenge any existing paradigms or develop new methodologies. This does not however weaken the application. Investigator: Dr. Guay-Woodford appears to have the technical and intellectual +____________ skills to accomplish the cloning of the cpk gene. Environment: The environment at University of Alabama School of Medicine +___________ appears to be conducive for the research proposed by the investigator. OVERALL EVALUATION: This proposal represents important steps that have to be +__________________ taken to further our understanding of the cpk locus. However the principal weakness of this proposal is Aim 1, the experiments designed do not answer the questions proposed by the PI. As already mentioned a more detailed experimental protocol is required to confirm or refute the speculations. Thus, it would be better to concentrate on the cloning of cpk gene.

magnetic resonance imaging; kidney imaging /visualization; kidney disorder diagnosis; polycystic kidney; diagnosis design /evaluation; gadolinium; patient oriented research; bioimaging /biomedical imaging; human subject; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Primary cilia are dynamic, complex structures that contain >250 proteins, including several polycystic kidney disease (PKD)-related proteins. In renal epithelial cells, the primary apical cilium appears to be a major effector of differentiation signals and to play a critical role in PKD pathogenesis. Recent in vitro studies demonstrate that the primary cilium acts as a cellular sensor, transducing apical mechanical signals through a polycystin-1/polycystin-2-dependent Ca++ signaling pathway. However, the precise mechanisms involved in cilia formation, stabilization, and signal transduction are not well-defined and even less is known about how these cilia-associated proteins are targeted to cilia and functionally assembled. We have identified Cys1 as the disease-gene in cpk mice; demonstrated that its novel protein product, cystin, localizes to the primary apical cilium; and determined that cystin fractionates with lipid rafts through an N-terminal domain, probably the predicted N-myristoylation/ polybasic motif. We hypothesize that cystin traffics to the primary cilium via lipid raft-mediated mechanisms, associates with the cilial membrane, and serves as part of the molecular framework that stabilizes the microtubular scaffold of the ciliary axoneme. Using a suite of stably transfected cell lines that express wild-type cystin and various truncation mutants as GFP-tagged fusion proteins, we have determined that the N-terminal domain is necessary but not sufficient for targeting cystin to cilia and a second, novel signal is required. Since cystin is expressed at low levels and no functional assays currently exist, we have developed an innovative set of strategies to further characterize this novel protein and its intracellular trafficking itinerary as first steps toward defining its function. Specifically, in this proposal, we will: 1) Determine whether cystin tagged with green fluorescent protein (cystin-GFP) rescues the cpk phenotype and targets correctly to the primary cilium of renal epithelia in vivo; 2) Characterize cystin with respect to the predicted N-myristoylation site, putative cilia-targeting signals, and putative interacting partners; and 3) Examine the dynamics of cystin intracellular trafficking to the primary apical cilium. The central hypotheses underlying the proposed studies are that defects in primary cilia function impair the terminal phases of renal tubulo-epithelial differentiation and the epithelial response to this developmental arrest is cyst formation. Therefore, primary apical cilium represents a new focal point for dissecting the complex mechanisms involved in renal cystic disease and ultimately, perhaps a new target for therapeutic interventions. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION: (provided by applicant) The University of Alabama at Birmingham (UAB) Recessive Polycystic Kidney Disease Core Center (DAB RPKDCC) will establish a UAB-based interdisciplinary center of excellence in PKD-related research, with specific emphasis on recessive PKD. The UAB RPKDCC builds on a core cadre of UAB investigators with established collaborations focused on investigations of human ARPKD and/or mouse models of recessive PKD. The Core Center expands to include outstanding investigators from UAB (Institutional Research Base), as well as multiple institutions in the US and Canada (Extended Research Base). The collective expertise of the assembled investigators has been organized into four thematic groups: 1) cilia-related biology, including calcium-mediated mechanotransduction pathways;2) regulation of epithelial transport pathways;3) signaling pathways that are critical in epithelial differentiation;and 4) matrix biology and fibrosis. These areas of emphasis incorporate the major mechanisms implicated in the pathogenesis of recessive PKD. The Core Center investigators will benefit from access to a set of five complementary Biomedical Research Cores that will integrate existing intellectual and technological resources of the University and provide a set of services/resources that will enable innovative investigations in the four thematic areas. The proposed biomedical cores are: 1) Core A - The ARPKD Clinical and Genetic Resource;2) Core B - The Engineered Mouse Resource;3) Core C - The Cellular Physiology Resource;4) Core D - The Tissue Characterization and Immunoreagent Resource;and 5) Core E - The Proteomic Resource. Taken together, these Cores and the extraordinary cohort of investigators assembled for this Center will provide the breadth and depth of expertise that is critical for innovative and productive research in recessive PKD. With its Extended Research Base that includes both clinical and basic investigators, this Core Center model will accelerate the translation of new investigative insights toward new therapies for ARPKD patients.

DESCRIPTION (provided by applicant): This application seeks partial support for the Federation of American Societies of Experimental Biology (FASEB) Summer Research Conference on "Polycystic Kidney Diseases: Molecular Pathways, Pathogenic Mechanisms and Translational Applications" to be held from August 6-11, 2005 in Saxtons River, VT. The planned conference follows a very successful, FASEB-sponsored inaugural conference that was held in August 2002. This meeting will highlight the exciting research progress in the interval three years, and thus provide a timely forum that integrates recent advances in basic research with applied themes. The conference will comprise a keynote address, nine regular scientific sessions, two 2-hour poster discussion sessions that will be organized based on the submitted abstracts (new, unpublished data), and a 2-hour session for late-breaking advances. The scientific program has been organized around three main themes. First, we will discuss the functional role of renal cystic disease proteins or cystoproteins in epithelial differentiation, polarity, and cell signaling, including their functional roles in signaling from the primary apical cilium. The second theme will take a broader view - examining cystoprotein function from a phylogenetic perspective; characterizing cystoprotein networks that are modulated by quantitative trait loci, and probing cystoprotein function in convergent pathways that have been implicated in phenotypically-diverse renal cystic diseases. The role of cystoproteins in non-renal epithelia and non-epithelial organs will also be explored. The final theme will have a translational focus - exploring biomarkers for disease progression and discussing targets for new and innovative therapies. The small size of the meeting (100-150 participants) with participants drawn from diverse disciplines ranging from nephrology and gasteroenterology, to cell biology and developmental biology, to molecular genetics and comparative genomics, to state-of-the-art imaging and pharmaceutical development, will provide an unparalleled opportunity for scientific cross-fertilization. By allowing ample time for scientific exchanges and critical discussion, the conference will serve as a conduit for exploring new experimental ideas and fostering new research collaborations.

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a relatively rare disorder, occurring in approximately 1 in 20,000 live births. Therefore, no single Center has sufficient patients for adequately powered clinical studies, genetic investigations, and/or therapeutic trials. Building on the established North American ARPKD Database and our extensive experience with mutational analysis of recessive PKD genes, including PKHD1, the objective of this Core: the ARPKD Clinical and Genetic Resource is to develop a unique set of clinical, genetic, and educational resources for ARPKD. This objective will be implemented in three specific aims. AIM 1 - Leverage the established North American ARPKD Database to build a comprehensive Clinical Database that includes all patients who meet the inclusion criteria for ARPKD. AIM 2 - Genotype children with classic ARPKD, as well as unusual recessive PKD phenotypes, for mutations in PKHD1 and/or the human orthologues of mouse recessive PKD genes and develop a Mutational Database. This Database will be capable of linking clinical and mutational information in a searchable format to facilitate genetic analyses (e.g. genotype-phenotype correlations, modifier gene studies), translational studies, and clinical trials. AIM 3 - Create a multi-media, web-based resource called "Understanding ARPKD". This Aim will address the paucity of reliable sources of information currently available to ARPKD families, their physicians, and genetic counselors. The distinctive feature of this Core is that it builds on clinical, genotyping, and educational programs already in place at UAB. Through the P30 mechanism, this Core will make these important resources available to the broader community of interested investigators, ARPKD families, and physicians/healthcare providers.

Idiopathic focal segmental glomerulosclerosis (FSGS) is a primary glomerular disorder that is often[unreadable] associated with refractory edema, severe infections, thromboembolic complications, and progression to[unreadable] end-stage renal disease. Evidence indicates that a diverse set of pathogenic mechanisms cause FSGS,[unreadable] most notably: 1) single-gene mutations in the genes encoding podocin (NPHS2) and WT-1; 2) a[unreadable] multifactorial defect that includes, but is not limited to, heterozygous mutations and polymorphisms in[unreadable] podocyte-related genes; and 3) a T-cell disorder that causes production of circulating permeability factor(s)[unreadable] which alters the filtration barrier. This pathogenetic heterogeneity has significant therapeutic implications.[unreadable] For example, in European studies, children and adults with two pathogenic NPHS2 mutations are steroidresistant[unreadable] and exhibit no, or at best, limited response to immunosuppressive agents such as cyclosporine[unreadable] (CsA).[unreadable] The NIDDK has initiated a prospective, controlled, randomized trial to compare the therapeutic response[unreadable] in children and adults with steroid-resistant FSGS treated with either CsA or mycophenolic mofetil (MMF).[unreadable] As an ancillary study to the FSGS Clinical Trial (FSGS-CT), the "Comprehensive Study of FSGS" has[unreadable] developed five interactive projects to further elucidate pathogenetic mechanisms and establish the platform[unreadable] for development of novel and targeted treatment strategies. Project 4 is designed: 1) to examine the FSGSCT[unreadable] cohort for mutations in podocyte-related genes; determine the prevalence of these mutations among[unreadable] patients in each therapeutic arm; and correlate mutations with response to either CsA or MMF; and 2) to[unreadable] examine the association between therapeutic response to CsA or MMF and DNA polymorphisms in genes[unreadable] involved in immunosuppressive action, podocyte structural biology, and fibrogenic pathways.[unreadable] The central hypotheses are: 1) this FSGS-CT cohort will have a significant percentage of patients with[unreadable] ingle-gene defects, predominantly in NPHS2. These patients will have no, or at best, limited response to[unreadable] further immunosuppressive treatment; and 2) genotypes/haplotypes of the major candidate genes involved in[unreadable] drug action/disposition (CsA and MMF), podocyte structural biology, and fibrogenic pathways will be[unreadable] predictive of therapeutic outcomes. Project 4 is the first study to examine these issues in the context of a[unreadable] large therapeutic trial involving North American FSGS patients. The genetic profiles defined in this[unreadable] ethnically and racially diverse cohort will guide the development of prospective, individualized treatment[unreadable] algorithms for FSGS patients, so as to optimize the likelihood of therapeutic response and minimize or avoid[unreadable] major drug-related adverse effects.[unreadable]

[unreadable] DESCRIPTION (provided by applicant): The International Developmental Nephrology Workshop was initiated in 1980 as a small meeting forum for investigators to exchange ideas and critically evaluate recent work focused on renal embryogenesis, postnatal functional development, and renal metabolism. The Workshop was an unqualified success and spurred the organization of subsequent triennual meetings that have become widely recognized as one of the premier small nephrology meetings. The 10th International Developmental Nephrology Workshop entitled "Molecular Networks: Programming Normal Renal Development and Modeling Disease Pathogenesis" represents the 10th international gathering of pediatric nephrologists, developmental biologists, developmental physiologists, cell biologists, and geneticists to discuss new scientific advances and engage in dynamic exchanges of ideas and concepts relating to the biology, pathophysiology, and genetics of the developing kidney and urinary tract. The current R13 application seeks funding to support travel awards for senior post-docs and fellows, as well as young investigators. While funding from foundations, corporate sponsors, and the International Pediatric Nephrology Association (IPNA) will cover the basic meeting expenses, the requested R13 funds will serve as our sole funding source for awarding up to 20 travel grants for senior trainees and junior investigators. We believe that the meeting format and the outstanding slate of speakers assembled for the 10th International Developmental Nephrology Workshop will provide a unique educational opportunity for qualified junior faculty and senior post-docs. Not only will they be exposed to cutting edge science, but the Workshop venue is highly conducive to small group discussions and interactions that should spark new collaborative interactions among the participants. The meeting will be held in Pecs, Hungary from August 27-30, 2007, immediately preceding the 14th IPNA Congress in Budapest, Hungary (August 31- September 4, 2007). [unreadable] [unreadable] [unreadable]

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. In 2007, the University of Alabama at Birmingham (DAB) and its affiliates completed three important, large- scale strategic planning efforts. Together, these processes generated a "blueprint for our research future" :hat lays the foundation to transform our substantial clinical and translational research enterprise through ntegration and innovation across all disciplines, Schools, and our health care system. This transformation will be driven by the DAB Center for Clinical and Translational Science (CCTS). The CCTS vision is to transform the DAB environment by building productive and efficient interdisciplinary research teams through educational ingenuity, regulatory reorganization, resource coordination, and methodological innovation. The mission is to develop a transformative infrastructure that spans the spectrum from preclinical research to bench-to-bedside translation (T1 research) to community implementation (T2 research), and will meet 5 goals: 1) transform the Investigator;2) transform the Training Environment;3) transform the Resource Infrastructure;4) transform the Approach to Interdisciplinary Research via an emphasis on outcomes research and health disparities research;and 5) establish a new Research Model through the Self-Monitoring and Improvement Program. To meet these goals, the CCTS will rely on: 1) a re-organized reporting structure that assures the PI full institutional support in implementing the CCTS roadmap;2) a revised CCTS leadership that includes faculty from the Schools of Medicine, Public Health, Nursing, Health Professions, and Optometry;and 3) innovative partnerships involving UAB, Southern Research Institute (our affiliated, not-for-profit research organization for preclinical drug discovery/development), the Children's Health System, the HudsonAlpha Institute for Biotechnology, the greater Birmingham community, and a long-standing collaborative network that involves Historically Black Colleges and Universities (HBCUs) and underprivileged communities in our region. UAB, the Health System, Health Services Foundation, Research Foundation, and Southern Research Institute have made substantial commitments to the CCTS including: 1) significant new funding for the clinical and translational research infrastructure (~$150 million, of which over $18 million are directly for CCTS activities and programs);2) a redesigned and enhanced biomedical informatics infrastructure;and 3) over 20,000 sf of prime clinical and administrative space. When combined, the re-organized CCTS governance and leadership, the substantial commitment of funds and resources, the interdisciplinary culture of UAB, and the new CCTS programs, will create a transformed environment for clinical and translational research that will benefit our trainees, investigators, patients, community, and the national CTSA effort.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. In 2007, the University of Alabama at Birmingham (DAB) and its affiliates completed three important, large- scale strategic planning efforts. Together, these processes generated a "blueprint for our research future" :hat lays the foundation to transform our substantial clinical and translational research enterprise through ntegration and innovation across all disciplines, Schools, and our health care system. This transformation will be driven by the DAB Center for Clinical and Translational Science (CCTS). The CCTS vision is to transform the DAB environment by building productive and efficient interdisciplinary research teams through educational ingenuity, regulatory reorganization, resource coordination, and methodological innovation. The mission is to develop a transformative infrastructure that spans the spectrum from preclinical research to bench-to-bedside translation (T1 research) to community implementation (T2 research), and will meet 5 goals: 1) transform the Investigator;2) transform the Training Environment;3) transform the Resource Infrastructure;4) transform the Approach to Interdisciplinary Research via an emphasis on outcomes research and health disparities research;and 5) establish a new Research Model through the Self-Monitoring and Improvement Program. To meet these goals, the CCTS will rely on: 1) a re-organized reporting structure that assures the PI full institutional support in implementing the CCTS roadmap;2) a revised CCTS leadership that includes faculty from the Schools of Medicine, Public Health, Nursing, Health Professions, and Optometry;and 3) innovative partnerships involving UAB, Southern Research Institute (our affiliated, not-for-profit research organization for preclinical drug discovery/development), the Children's Health System, the HudsonAlpha Institute for Biotechnology, the greater Birmingham community, and a long-standing collaborative network that involves Historically Black Colleges and Universities (HBCUs) and underprivileged communities in our region. UAB, the Health System, Health Services Foundation, Research Foundation, and Southern Research Institute have made substantial commitments to the CCTS including: 1) significant new funding for the clinical and translational research infrastructure (~$150 million, of which over $18 million are directly for CCTS activities and programs);2) a redesigned and enhanced biomedical informatics infrastructure;and 3) over 20,000 sf of prime clinical and administrative space. When combined, the re-organized CCTS governance and leadership, the substantial commitment of funds and resources, the interdisciplinary culture of UAB, and the new CCTS programs, will create a transformed environment for clinical and translational research that will benefit our trainees, investigators, patients, community, and the national CTSA effort.

In 2007, the University of Alabama at Birmingham (DAB) and its affiliates completed three important, large- scale strategic planning efforts. Together, these processes generated a "blueprint for our research future" that lays the foundation to transform our substantial clinical and translational research enterprise through ntegration and innovation across all disciplines, Schools, and our health care system. This transformation will be driven by the UAB Center for Clinical and Translational Science (CCTS). The CCTS vision is to transform the UAB environment by building productive and efficient interdisciplinary research teams through educational ingenuity, regulatory reorganization, resource coordination, and methodological innovation. The mission is to develop a transformative infrastructure that spans the spectrum from preclinical research to bench-to-bedside translation (T1 research) to community implementation (T2 research), and will meet 5 goals: 1) transform the Investigator; 2) transform the Training Environment; 3) transform the Resource Infrastructure; 4) transform the Approach to Interdisciplinary Research via an emphasis on outcomes research and health disparities research; and 5) establish a new Research Model through the Self-Monitoring and Improvement Program. To meet these goals, the CCTS will rely on: 1) a re-organized reporting structure that assures the PI full institutional support in implementing the CCTS roadmap; 2) a revised CCTS leadership that includes faculty from the Schools of Medicine, Public Health, Nursing, Health Professions, and Optometry; and 3) innovative partnerships involving UAB, Southern Research Institute (our affiliated, not-for-profit research organization for preclinical drug discovery/development), the Children's Health System, the HudsonAlpha Institute for Biotechnology, the greater Birmingham community, and a long-standing collaborative network that involves Historically Black Colleges and Universities (HBCUs) and underprivileged communities in our region. UAB, the Health System, Health Services Foundation, Research Foundation, and Southern Research Institute have made substantial commitments to the CCTS including: 1) significant new funding for the clinical and translational research infrastructure (~$150 million, of which over $18 million are directly for CCTS activities and programs); 2) a redesigned and enhanced biomedical informatics infrastructure; and 3) over 20,000 sf of prime clinical and administrative space. When combined, the re-organized CCTS governance and leadership, the substantial commitment of funds and resources, the interdisciplinary culture of UAB, and the new CCTS programs, will create a transformed environment for clinical and translational research that will benefit our trainees, investigators, patients, community, and the national CTSA effort.

In 2007, the University of Alabama at Birmingham (UAB) and its affiliates completed three important, large- scale strategic planning efforts. Together, these processes generated a "blueprint for our research future" that lays the foundation to transform our substantial clinical and translational research enterprise through integration and innovation across all disciplines, Schools, and our health care system. This transformation will be driven by the UAB Center for Clinical and Translational Science (CCTS). The CCTS vision is to transform the UAB environment by building productive and efficient interdisciplinary research teams through educational ingenuity, regulatory reorganization, resource coordination, and methodological innovation. The mission is to develop a transformative infrastructure that spans the spectrum from preclinical research to bench-to-bedside translation (T1 research) to community implementation (T2 research), and will meet 5 goals: 1) transform the Investigator;2) transform the Training Environment;3) transform the Resource Infrastructure;4) transform the Approach to Interdisciplinary Research via an emphasis on outcomes research and health disparities research;and 5) establish a new Research Model through the Self-Monitoring and Improvement Program. To meet these goals, the CCTS will rely on: 1) a re-organized reporting structure that assures the PI full institutional support in implementing the CCTS roadmap;2) a revised CCTS leadership that includes faculty from the Schools of Medicine, Public Health, Nursing, Health Professions, and Optometry;and 3) innovative partnerships involving UAB, Southern Research Institute (our affiliated, not-for-profit research organization for preclinical drug discovery/development), the Children's Health System, the HudsonAlpha Institute for Biotechnology, the greater Birmingham community, and a long-standing collaborative network that involves Historically Black Colleges and Universities (HBCUs) and underprivileged communities in our region. UAB, the Health System, Health Services Foundation, Research Foundation, and Southern Research Institute have made substantial commitments to the CCTS including: 1) significant new funding for the clinical and translational research infrastructure (~$150 million, of which over $18 million are directly for CCTS activities and programs);2) a redesigned and enhanced biomedical informatics infrastructure;and 3) over 20,000 sf of prime clinical and administrative space. When combined, the re-organized^ CCTS governance and leadership, the substantial commitment of funds and resources, the interdisciplinary culture of UAB, and the new CCTS programs, will create a transformed environment for clinical and translational research that will benefit our trainees, investigators, patients, community, and the national CTSA effort.

Infrastructure; Pediatric Research; Research Infrastructure

Infrastructure; Research; Research Infrastructure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CTSA infrastructure for clinical trials and pediatric research.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This supplemental award provides funds to CTSA Consortium-supported research projects for research on outcome measures in clinical and translational child health in priority areas as determined by the Best Pharmaceuticals for Children Act (BPCA) program administered by NICHD.

DESCRIPTION, OVERALL (provided by applicant): The University of Alabama at Birmingham (UAB) Hepato/Renal Fibrocystic Diseases Core Center (UAB HRFDCC) will expand our previous P30-funded, interdisciplinary center of excellence in recessive PKD related research, to encompass ARPKD, as well as other single-gene disorders that comprise the hepato/renal fibrocystic diseases spectrum. The UAB HRFDCC will provide the impetus and the engine necessary to drive innovation, training, productivity, and new discovery within a North American network of investigators focused on this spectrum of disorders. The participating faculty includes outstanding investigators from UAB and MUSC (Institutional Research Base), as well as multiple institutions in the US and Canada (Extended Research Base). Each faculty member has a focused research effort in one of the Center's four thematic areas;1) cilia-related biology;2) regulation of epithelial transport;3) epithelial differentiation signaling pathways;and 4) matrix biology and fibrosis. To support and enhance innovative research efforts by these investigators, a set of four complementary Biomedical Research Cores that integrate existing intellectual and technological resources of UAB and MUSC are provided: 1) Core A: The Hepto/Renal Fibrocystic Diseases Translational Resource;2) Core B: The Engineered Models Resource;3) Core C: The Cellular Physiology Resource;and 4) Core D: The Immunoreagent and Structural Characterization Resource. In addition, three well-designed Pilot projects are proposed, each of which use novel approaches to address important mechanistic questions in hepato/renal fibrocystic diseases. An Educational Enrichment Program will facilitate interactions and enhance collaborative opportunities among the research base. Taken together, the Center Cores and the extraordinary cohort of assembled investigators will provide the breadth and depth of expertise that is critical for innovative and productive research. Significant added value comes from the Extended Research Base that includes both clinical and basic investigators, with this Core Center model accelerating the translation of new investigative insights toward new therapies for patients with hepato/renal fibrocystic diseases, particularly ARPKD. Public Health Relevance: The hepato/renal fibrocystic diseases are important causes of childhood morbidity and mortality. The UAB HRFDCC will apply state-of-the-art methodologies in a cost-effective manner to address experimental questions that will: 1) advance understanding disease pathogenesis, 2) enhance diagnostic specificity, and 3) facilitate new therapeutic approaches in the hepato/renal fibrocystic diseases, particularly ARPKD.

PROJECT SUMMARY Autosomal recessive polycystic kidney disease (ARPKD) and other hepato-renal fibrocystic diseases (HRFD) are relatively rare recessive disorders, but constitute an important set of childhood nephropathies. Rare disease research requires greater collaboration than the efforts in common diseases where patient resources are routinely available and large repositories can be built locally. For the HRFD, experimental studies would be well served by case accrual that coordinates collection of clinical data, bio-specimens (DNA and tissues) and mutational information. The centralization and sharing of clinical and genetic information, as well as bio-materials, can provide a critical impetus for more rapid progress by the research community. In this competitive renewal, we will continue to compile baseline and longitudinal clinical information in our HRFD Clinical Database; expand our bio-materials (DNA and tissue) repositories; and deploy new strategies to identify genetic mutations in ARPKD and other HFRD patients, including new tools to interpret PKHD1 missense variants. Clinical and genetic data, as well as patient bio-specimens, will be drawn from tertiary care centers throughout the Americas (North, Central, and South). Finally, we will utilize the learning management system established in our CTSA-funded program to establish a multi-modality resource for our expanding portfolio of HRFD-related educational information and tools. Our goal for this renewal application is to acquire a sufficient volume of clinical data, biological specimens, and genomic information in a centralized resource to accelerate discovery research in human HRFD and integrate the resulting data in an enabling platform for developing new, targeted interventional strategies, assessing genotype-phenotype correlations, and identifying new disease genes by our Investigator User Base, as well as other members of the research community.  

ABSTRACT It is the goal of the UAB-Childhood Cystic Kidney Disease Core Center (CCKDCC) to work with the other U54 PKD Centers, under the direction of the U24 Coordinating Center Site (U24-CCS) to reduce obstacles in cystic kidney disease research leading to more rapid translational studies by PKD Consortium Members and development of novel therapeutics. The UAB-CCKDCC will help address the limitations associated with the small CCKD patient population available at individual intuitions by providing access to clinical data and biomaterial from human CCKD patients from across the Americas. The Center will focus on the development of resources to analyze cilio-cystic disease protein function, localization, and interactions. The UAB-CCKDCC has assembled a multidisciplinary team of researchers to carry out these goals and actively recruit new and established investigators to the field. The Center will generate and provide researchers with patient relevant models of CCKD and establish methodology to utilize these models to ascertain the efficacy of candidate therapies to slow disease progression using a standardized, cost-effective, and longitudinal imaging strategy. The resources provided by the CCKDCC will help address several of the most significant hurdles slowing the development of therapeutic approaches and strategically recruit new scientists into the field. The Clinical, Translational, and Biorepository Resource (Core A) will compile clinical data, genetic information, and biological specimens from patients with recessive HRFD, as well as launch the US node of ADPedKD, an international, multicenter observational study of childhood ADPKD. This centralized resource is designed to accelerate discovery research in childhood cystic kidney diseases (partnership with Cores B and C). Integration of these resources under a unique identifier, combined with rigorous, detailed interviews of patient/caregiver health research experiences will inform the development of new, targeted interventional strategies (partnership with Core D). The Core will coordinate efforts with other U54-RTCCs, under direction of the U24-CCS and NIDDK, to develop and make the resources available to the PKD Research Consortium.