Source: CORNELL UNIVERSITY submitted to
HERITABLE DISEASES OF CONNECTIVE TISSUE
Sponsoring Institution
Cooperating Schools of Veterinary Medicine
Project Status
EXTENDED
Funding Source
Reporting Frequency
Annual
Accession No.
0079221
Grant No.
(N/A)
Project No.
NYCV-435368
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Mar 31, 1982
Project End Date
Dec 31, 2009
Grant Year
(N/A)
Project Director
Minor, R.
Recipient Organization
CORNELL UNIVERSITY
(N/A)
ITHACA,NY 14853
Performing Department
Biomedical Sciences
Non Technical Summary
(N/A)
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
3113899100050%
3113899116050%
Goals / Objectives
This is a study of structural and metabolic defects in procollagen and other matrix proteins in genetic diseases of connective tissues of humans and domestic animals (bovine, ovine, equine, canine and feline).
Project Methods
Abnormalities in the structure and metabolism of procollagen will be identified and characterized in ascorbate stimulated post-confluent cultures of skin and tendon fibroblasts, and in collagens and procollagens extracted from affected tissues. A variety of biochemical techniques will be used to study the effects of each mutation on collagen synthesis, post-translational modification, secretion, extracellular processing to collagen, and covalent cross-linking of collagen into fibrils. Both regulatory and structural defects in matrix proteins will be correlated with studies the corresponding genes in collaborative studies with molecular geneticists. At the same time biochemical defects in matrix proteins will be correlated with the results of light and electron microscopic studies of defects in the packing of collagen into fibrils and fibers, and with the results of biomechanical studies of the tissue fragility that is the primary characteristic of diseases of collagen.

Progress 12/01/87 to 12/31/88

Outputs
Abnormalities in the structure and metabolism of procollagen will be identified and characterized in ascorbate stimulated post-confluent cultures of skin and tendon fibroblasts, and in collagens and procollagens extracted from affected tissues. A variety of biochemical techniques will be used to study the effects of each mutation on collagen synthesis, post-translational modification, secretion, extracellular processing to collagen, and covalent cross-linking of collagen into fibrils. Both regulatory and structural defects in matrix proteins will be correlated with studies the corresponding genes in collaborative studies with molecular geneticists. At the same time biochemical defects in matrix proteins will be correlated with the results of light and electron microscopic studies of defects in the packing of collagen into fibrils and fibers, and with the results of biomechanical studies of the tissue fragility that is the primary characteristic of diseases of collagen.

Impacts
(N/A)

Publications


    Progress 01/01/87 to 12/30/87

    Outputs
    This is a study of heritable diseases of connective tissues. It is focused on identification and characterization of abnormalities in the production, organization & maintenance of collagen fibrils & fibers. This includes collagen in skin, tendon, ligaments & fascia, as well as in bones & teeth. This includes diseases in animals that are analogs of the Ehlers Danlos syndrome (EDS) & osteogenesis imperfecta in humans. Our genetics studies show that these diseases are usually autosomal dominant traits, but they have also been shown to occur as autosomal rescessive & x-linked traits in sheep, cattle, horses, dogs, cats, mink, mice & man. Biochemical studies show that the tensile strength of affected skin was less than 10% of normal, & electron microscopy shows that the tissue fragility results from defects in either the formation or degradation of collagen fibrils & fibers. Biochemical studies show that each new variant appears to result from a different abnormality. In any one variant there may or may not be a decrease in the amount of collagen per unit area of skin, may or may not be an abnormality in the primary structure of collagen, may or may not be an increase in the solubility of collagen & may or may not be an increase in collagenase activity in affected skin.

    Impacts
    (N/A)

    Publications


      Progress 07/01/86 to 12/30/86

      Outputs
      This is a study of heritable diseases of connective tissues. It is focused on identification and characterization of abnormalities in the production, organization and maintenance of collagen fibrils and fibers. This includes collagen in skin, tendon, ligaments and fascia, as well as in bones and teeth. This includes diseases in animals that are analogs of the Ehlers Danlos syndrome (EDS) and osteogenesis imperfecta in humans. Our genetic studies show that these diseases are usually autosomal dominant traits, but they have also been shown to occur as autosomal recessive and X-linked traits in sheep, cattle, horses, dogs, cats, mink, mice and man. Biomechanical studies show that the tensile strength of affected skin was less than 10% of normal, and electron microscopy shows that the tissue fragility results from defects in either the formation or degradation of collagen fibrils and fibers. Biochemical studies show that each new variant appears to result from a different abnormality. In any one variant there may or may not be a decrease in the amount of collagen per unit area of skin, may or may not be an abnormality in the primary structure of collagen, may or may not be an increase in the solubility of collagen and may or may not be an increase in collagenase activity in affected skin.

      Impacts
      (N/A)

      Publications


        Progress 01/01/85 to 12/30/85

        Outputs
        This is a study of heritable diseases that cause connective tissues to be fragile and/or hyperextensible. Since collagen is the primary source of tensile strength of tissues, this is primarily a study of the production, organization and maintenance of collagen fibrils and fibers in diseases affecting fibrous tissues such as skin, tendon, ligaments and fascia, as well as in bones and teeth. This includes diseases in animals that are analogs of the Ehlers Danlos syndrome (EDS) and osteogenesis imperfecta in humans. Our genetic studies show that these diseases are usually autosomal dominant traits, but they have also been shown to occur as autosomal recessive and X-linked traits in sheep, cattle, horses, dogs, cats, mink, mice and man. Electron microscopy shows that in the autosomal dominant analogs of EDS, the tissue fragility results from defects in either the formation or degradation of collagen fibrils and fibers. For example, biomechanical studies with uniaxial tension testing showed that the tensile strength of affected skin was less than 10% of normal in the dogs and cats with abnormal packing of collagen into fibrils and fibers, while biochemical studies showed that there was no decrease in the amount of collagen per unit area of skin, no abnormality in the primary structure of collagen, and no abnormality in the solubility or resistance of collagen to proteolysis in affected skin.

        Impacts
        (N/A)

        Publications


          Progress 01/01/83 to 12/30/83

          Outputs
          This is a study of heritable diseases affecting collagen in both companion and food and fiber producing animals. Collagen constitutes one third of the total body protein and heritable defects involving collagen have been identified in sheep, cattle, horses, mink, dogs, cats and man. An autosomal recessive deficiency in procollagen N-peptidase results in a defect in collagen fibrillogenesis and leads to hyperextensible fragile skin in sheep, cattle and man. Autosomal dominent defects in collagen fibrillogenesis resulting in fragile hyperextensible skin have also been identified in mink, dogs, cats, horses, sheep and man. Electron microscopy has been used to characterize the defect in the packing of collagen in biopsy specimens from an affected horse, sheep, dog and cat, and colonies of both cats and dogs have been developed for breeding studies and biochemical analyses of the defect in the packing of collagen into fibrils and fibers. Electron microscopy has shown that there is a loss of the control of lateral growth of collagen fibrils in skin, fascia and tendon, as well as a severe disorganization of the packing of collagen fibrils into fibrils in the skin. Breeding studies in cats have shown that this defect is lethal during the early organogenetic period of homozygous embryos but the fragile hyperextensible skin is the only clinical defect in heterozygous animals. Recent studies have also shown that there is a decrease in total bone mass in heterozygous dogs and cats.

          Impacts
          (N/A)

          Publications


            Progress 01/01/82 to 12/30/82

            Outputs
            This is a study of heritable diseases affecting collagen in both companion and food and fiber producing animals. Collagen constitutes one third of the total body protein and heritable defects involving collagen have been identified in sheep, cattle, horses, mink, dogs, cats and man. An autosomal recessive deficiency in procollagen N-peptidase results in a defect in collagen fibrillogenesis and leads to hyperextensible fragile skin in sheep, cattle and man. Autosomal dominant defects in collagen fibrillogenesis resulting in fragile hyperextensible skin have also been identified in mink, dogs, cats, horses, sheep and man. Due to the economics of care and breeding, the primary model being used in this study is one of the autosomal dominant defects in collagen fibrillogenesis in the dog and cat. Electron microscopy has been used to characterize the defect in the packing of collagen in biopsy specimens from an affected horse, sheep, dog and cat, and colonies of both cats and dogs have been developed for breeding studies and biochemical analyses of the defect in the packing of collagen into fibrils and fibers. Electron microscopy has shown that there is a loss of the control of lateral growth of collagen fibrils in skin, fascia and tendon, as well as a severe disorganization of the packing of collagen fibrils into fibers in the skin.

            Impacts
            (N/A)

            Publications


              Progress 01/01/81 to 12/30/81

              Outputs
              This is a study of heritable diseases affecting collagen in both companion and food and fiber producing animals. Collagen constitutes one third of the total body protein and heritable defects involving collagen have been identified in sheep, cattle, horses, mink, dogs, cats and man. An autosomal recessive deficiency in procollagen N-peptidase results in a defect in collagen fibrillogenesis and leads to hyperextensible fragile skin in sheep, cattle and man. Autosomal dominant defects in collagen fibrillogenesis resulting in fragile hyperextensible skin have also been identified in mink, dogs, cats, horses, sheep and man. Due to the economics of care and breeding, the primary model being used in this study is one of the autosomal dominant defects in collagen fibrillogenesis in the dog and cat. Electron microscopy has been used to characterize the defect in the packing of collagen in biopsy specimens from an affected horse, sheep, dog and cat, and colonies of both cats and dogs have been developed for breeding studies and biochemical analyses of the defect in the packing of collagen into fibrils and fibers. Electron microscopy has shown that there is a loss of the control of lateral growth of collagen fibrils in skin, fascia and tendon, as well as a severe disorganization of the packing of collagen fibrils into fibers in the skin.

              Impacts
              (N/A)

              Publications


                Progress 01/01/80 to 12/30/80

                Outputs
                This is a study of heritable diseases affecting collagen in both companion and food and fiber producing animals. Collagen constitutes one-third of the total body protein and heritable defects involving collagen have been identified in sheep, cattle, horses, mink, dogs, cats and man. An autosomal recessive deficiency in procollagen N-peptidase results in a defect in collagen fibrillogenesis and leads to hyperextensible fragile skin in sheep, cattle and man. Autosomal dominant defects in collagen fibrillogenesis resulting in fragile hyperextensible skin have also been identified in mink, dogs, cats, horses, sheep and man. Due to the economics of care and breeding, the primary model being used in this study is one of the autosomal dominant defects in collagen fibrillogenesis in the dog and cat. Electron microscopy has been used to characterize the defect in the packing of collagen in biopsy specimens from an affected horse, sheep, dog and cat, and colonies of both cats and dogs have been developed for breeding studies and biochemical analyses of the defect in the packing of collagen into fibrils and fibers. Electron microscopy has shown that there is a loss of the control of lateral growth of collagen fibrils in skin, fascia and tendon, as well as a severe disorganization of the packing of collagen fibrils into fibers in the skin.

                Impacts
                (N/A)

                Publications


                  Progress 01/01/79 to 12/30/79

                  Outputs
                  This is a study of heritable diseases affecting collagen in both companion and food and fiber producing animals. Collagen constitutes one-third of the total body protein and heritable defects involving collagen have been identified in sheep, cattle, horses, mink, dogs, cats and man. An autosomal recessive deficiency in procollagen peptidase N results in a defect in collagen fibrillogenesis and leads to hyperextensible fragile skin in sheep, cattle and man. Autosomal dominant defects in collagen fibrillogenesis resulting in fragile hyperextensible skin have also been identified in mink, dogs, cats, horses, sheep and man. Due to the economics of care and breeding, the primary model being used in this study is one of the autosomal dominant defects in collagen fibrillogenesis in the dog and cat. Electron microscopy has been used to characterize the defect in the packing of collagen in biopsy specimens from an affected horse, sheep, dog and cat, and a colony of cats has been developed for breeding studies and biochemical analyses of the defect in the packing of collagen into fibrils and fibers. Electron microscopy has shown that there is a loss of the control of lateral growth of collagen fibrils in skin, fascia and tendon, as well as a severe disorganization in the packing of collagen fibrils into fibers in the skin.

                  Impacts
                  (N/A)

                  Publications